For patients with lymphoma that recurs after chemotherapy, bone marrow transplantation using
cells from a healthy donor represents potentially curative treatment. In these individuals,
cure is possible because transplantation of healthy donor immune cells can fight the
lymphoma in the patient. The goal of this work is to test a strategy that activates the
healthy donor immune cells so that they more effectively fight lymphoma and can result in an
increased cure rate for these patients. Our group has previously studied CpG, an immune
activating medication, in patients with lymphoma and demonstrated modest anti-tumor
responses. We now have a more potent form of CpG which we intend to test to see if it will
better activate the donor immune cells and result in shrinkage of tumor throughout the
entire body, not just at the injected site.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, 650-723-0822.

RATIONALE: Lenalidomide may stop the growth of mycosis fungoides/Sezary syndrome by blocking
blood flow to the cancer.
PURPOSE: This phase II trial is studying how well lenalidomide works in treating patients
with relapsed mycosis fungoides/Sezary syndrome.

Stanford is currently not accepting patients for this trial.For more information, please contact Natalie Viakhireva, (650) 723 - 8949.

The study objective is to demonstrate that the UVADEX® Sterile Solution formulation of
methoxsalen used in conjunction with the UVAR XTS Photopheresis System can have a clinical
effect on the skin manifestations of CTCL (mycosis fungoides) in early stage disease.

Stanford is currently not accepting patients for this trial.For more information, please contact Natalie Viakhireva, (650) 723 - 8949.

This study will determine the maximum dose of KW-0761 administered intravenously that can be
given safely in subjects with previously treated peripheral T-cell lymphoma (PTCL) or
cutaneous T-cell lymphoma(CTCL)and will see if it is effective in treating the disease.

Stanford is currently not accepting patients for this trial.For more information, please contact Katie Turner, (650) 725 - 1202.

The purpose of the study is to evaluate the feasibility and safety of transplanting CD34+
selected hematopoietic cells from a haploidentical related donor following a
nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin
(ATG).

Stanford is currently not accepting patients for this trial.For more information, please contact BMT Referrals, (650) 723 - 0822.

Chemotherapy Based on PET Scan in Treating Patients With Stage I or Stage II Hodgkin LymphomaNot Recruiting

RATIONALE: Drugs used in chemotherapy, such as doxorubicin hydrochloride, bleomycin sulfate,
vinblastine, dacarbazine, cyclophosphamide, etoposide, procarbazine hydrochloride,
vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer
cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses
high-energy x rays to kill cancer cells. Giving combination chemotherapy together with
radiation therapy may kill more cancer cells. Comparing results of imaging procedures, such
as PET scans and CT scans, done before, during, and after chemotherapy may help doctors
predict a patient's response to treatment and help plan the best treatment.
PURPOSE: This phase II clinical trial studies how well chemotherapy based on PET/CT scan
works in treating patients with stage I or stage II Hodgkin lymphoma.

Stanford is currently not accepting patients for this trial.For more information, please contact Maria Pitsiouni, (650) 721 - 6977.

A Single Agent Phase II Study of Romidepsin (Depsipeptide, FK228) in the Treatment of Cutaneous T-cell Lymphoma (CTCL)Not Recruiting

GPI-04-0001 was a Phase II, non-randomized, open label, single arm study that was conducted
at approximately 30 sites, primarily in the United States, Europe and Russia. It assessed
the efficacy, safety, and tolerability of romidepsin as a treatment for cutaneous T-cell
lymphoma (CTCL). Study patients (pts) received romidepsin in a dose of 14 mg/m^2
intravenously over 4 hours on Days 1, 8 and 15 of each 28-day cycle. The duration of study
treatment was 6 cycles although pts who showed an objective response or stable disease could
continue to receive therapy, at the discretion of the investigator, until disease
progression or another withdrawal criterion was met.

Stanford is currently not accepting patients for this trial.For more information, please contact Sunil Arani Reddy, (650) 736 - 1234.

Phase I/II Study of Intratumoral Injection of CPG 7909, a TLR9 Agonist, Combined With Local Radiation for Patients With Recurrent Mycosis Fungoides.Not Recruiting

This is a single institution phase I / II trial to evaluate the safety and efficacy of
intratumoral CpG injections combined with local radiation in patients with mycosis
fungoides. Patients will receive low-dose radiotherapy to a single tumor site on days 1 and
2 (2 Gy each day). CpG injections will be administered into the same tumor site within 24
hours before or 24 hours after each radiation treatment. Weekly doses of (intratumoral or
peritumoral injections) CpG will be then administered subcutaneously in the region of
previous injections for 23 additional doses. The total treatment duration is 24 weeks.

Stanford is currently not accepting patients for this trial.For more information, please contact Mayita Romero, (650) 725 - 6452.

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing
so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor
cells. Combining chemotherapy with radiation therapy may kill more tumor cells.
PURPOSE: This phase II trial is studying how well giving combination chemotherapy together
with low-dose radiation therapy works in treating patients with stage I or stage IIA
Hodgkin's lymphoma.

Stanford is currently not accepting patients for this trial.For more information, please contact Anne Wiley, (650) 725 - 6432.

The purpose of this study is to determine the efficacy of the drug, HuMax-CD4, in patients
with mycosis fungoides(MF) and sezary syndrome who are intolerant to or do not respond to
treatment with Targretin® and one other standard therapy.

Stanford is currently not accepting patients for this trial.For more information, please contact Daniel Navi, (650) 736 - 2300.

RATIONALE: Monoclonal antibodies such as rituximab can locate tumor cells and either kill
them or deliver tumor-killing substances to them without harming normal cells.
PURPOSE: Phase II trial to study the effectiveness of rituximab in treating patients who
have Hodgkin's lymphoma.

Stanford is currently not accepting patients for this trial.For more information, please contact Sarah Daadi, (650) 725 - 6456.

This is an open label, randomized phase II study designed to evaluate the tolerability and
response rate of high-dose and low-dose regimens in patients with advanced cutaneous T-cell
lymphoma (CTCL) who have had progressive, recurrent, or persistent disease on or following 2
systemic therapies.

Stanford is currently not accepting patients for this trial.For more information, please contact Daniel Navi, (650) 736 - 2300.

The Stanford Medical Center Program in Multi-Organ Transplantation and the Division of Bone
marrow Transplantation are enrolling patients into a research study to determine if donor
stem cells given after a living related one Haplotype match kidney transplantation will
change the immune system such that immunosuppressive drugs can be completely withdrawn.

Autologous Followed by Non-myeloablative Allogeneic Transplantation for Non-Hodgkin's LymphomaNot Recruiting

The purpose of this trial is to develop an alternative treatment for patients with poor risk
non-Hodgkin's lymphoma. This trial uses a combination of high dose chemotherapy with stem
cell transplant using the patient's own cells. This is followed with non-myeloablative
transplant using stem cells from a related or unrelated donor to try and generate an
anti-lymphoma response from the new immune system.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, 650-723-0822.

RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different
ways. Some find cancer cells and help kill them or carry cancer-killing substances to them.
Others interfere with the ability of cancer cells to grow and spread. Drugs used in
chemotherapy, such as bendamustine hydrochloride, also work in different ways to kill cancer
cells or stop them from dividing. Bortezomib may stop the growth of cancer cells by blocking
some of the enzymes needed for cell growth. Lenalidomide may stop the growth of mantle cell
lymphoma by blocking blood flow to the cancer. It is not yet known whether giving rituximab
together with bendamustine and bortezomib is more effective than rituximab and bendamustine,
followed by rituximab alone or with lenalidomide in treating mantle cell lymphoma.
PURPOSE: This randomized phase II trial studies rituximab, bortezomib, bendamustine, and
lenalidomide in treating previously untreated older patients with mantle cell lymphoma.

Stanford is currently not accepting patients for this trial.For more information, please contact Ekaterina Dib, 650-723-0503.

Study of Pralatrexate in Patients With Relapsed or Refractory Cutaneous T-cell LymphomaNot Recruiting

This study is being conducted to identify how much and how often pralatrexate, given with
vitamin B12 and folic acid, can be given safely to patients with cutaneous T-cell lymphoma
(CTCL) that has relapsed (returned after responding to previous treatment) or is refractory
(has not responded to previous treatment). It is also being conducted to get information on
whether or not pralatrexate is effective in treating relapsed or refractory CTCL.

Stanford is currently not accepting patients for this trial.For more information, please contact Cameron Harrison, (650) 721 - 7186.

Forodesine in the Treatment of Cutaneous T-Cell LymphomaNot Recruiting

This is a Phase II, non-randomized, open-label, single-arm trial that will be conducted at
up to 50 sites in North America, Europe and Australia. This study is designed to assess
objective response (OR) [complete response (CR) or partial response (PR)] in subjects with
cutaneous manifestations of CTCL with a requirement for maintenance of such objective
response for at least 28 days in subjects with stage IIB, III, and IVA CTCL. Additionally,
this study will evaluate the safety and tolerability of CTCL subjects Stages IB, IIA, IIB,
III, or IVA treated with oral forodesine.

Stanford is currently not accepting patients for this trial.For more information, please contact Natalie Viakhireva, (650) 723 - 8949.

We hope to learn whether I-131 tositumomab combined with external beam radiation therapy is
an effective means of treating relapsed, bulky non-Hodgkin's lymphoma. The purpose of the
study is to determine the overall response rate with responses described as: Site-dependent
and overall CR and functional CR (CR of CRu(Complete Response Unconfirmed)/PR with PET
negativity), or PR rates.

Stanford is currently not accepting patients for this trial.For more information, please contact Lucy Schoen, (650) 725 - 1718.

Extension Study in Subjects Who Relapsed After Complete Response on Study KW-0761-001Not Recruiting

This study will enroll subjects with either Peripheral T-Cell Lymphoma (PTCL) or Cutaneous
T-Cell Lymphoma(CTCL),including mycosis fungoides (MF) and Sezary Syndrome (SS), who have
relapsed after achieving a complete response in study, KW-0761-001.

Stanford is currently not accepting patients for this trial.For more information, please contact Cutaneous Lymphoma Coordinator, (650) 421 - 6370.

An Open Label Study to Evaluate the Safety and Efficacy of Mechlorethamine(MCH) 0.04% Formulation in Mycosis FungoidesNot Recruiting

To evaluate the efficacy and safety of topical application of MCH 0.04% in a propylene
glycol ointment (PG)in patients with stage I or IIA MF previously treated with MCH 0.02% in
a PG or AP ointment who did not achieve a complete response.

Stanford is currently not accepting patients for this trial.For more information, please contact Kokil Bakshi, (650) 421 - 6370.

Pralatrexate and Bexarotene in Patients With Relapsed or Refractory Cutaneous T-cell LymphomaNot Recruiting

This study is designed to determine the recommended dose, safety, pharmacokinetics, and
early efficacy of the combination of pralatrexate plus oral bexarotene in patients with
relapsed or refractory CTCL.

Stanford is currently not accepting patients for this trial.For more information, please contact Cutaneous Lymphoma Coordinator, (650) 421 - 6370.

The purpose of this study is to learn the effects of an investigational medication, SGN 35,
on patients with mycosis fungoides. Despite a wide range of therapeutic options, the
treatments are associated with short response duration, thus this condition is largely
incurable. This investigational drug may offer less toxicity than standard treatments and
have better tumor specific targeting.

Stanford is currently not accepting patients for this trial.For more information, please contact Kokil Bakshi, 650-421-6370.

The purpose of this study is to investigate the safety and tolerability of topical SHP141
applied directly to skin lesions in patients with Stage IA, IB, or IIA Cutaneous T-cell
Lymphoma. This study will also investigate the effect of SHP141 on skin lesions in patients
with Stage IA, IB, or IIA CTCL.

Stanford is currently not accepting patients for this trial.For more information, please contact Illisha Rajasansi, 650-421-1397.

Non-myeloablative approach for allogeneic transplant is a reasonable option, especially
given that the median age at diagnosis is 55-60 years and frequently present compromised
skin in these patients, which increases the risk of infection. Therefore, we propose a
clinical study with allogeneic HSCT using a unique non-myeloablative preparative regimen,
TLI/ATG, to treat advanced MF/SS.

Abstract

In the United States, early-stage Hodgkin's lymphoma (HL) is defined as asymptomatic stage I/II non-bulky disease. European groups stratify patients to more intense treatment by considering additional unfavorable factors, such as age, number of nodal sites, sedimentation rate, extranodal disease, and elements of the international prognostic score for advanced HL. We sought to determine the prognostic significance of these factors in patients with early-stage disease treated at Stanford University Medical Center.This study was a retrospective analysis of 101 patients treated with abbreviated Stanford V chemotherapy (8 weeks) and 30-Gy (n=84 patients) or 20-Gy (n=17 patients) radiotherapy to involved sites. Outcomes were assessed after applying European risk factors.At a median follow-up of 8.5 years, freedom from progression (FFP) and overall survival (OS) rates were 94% and 97%, respectively. From 33% to 60% of our patients were unfavorable per European criteria (i.e., German Hodgkin Study Group [GHSG], n=55%; European Organization for Research and Treatment of Cancer, n=33%; and Groupe d'Etudes des Lymphomes de l'Adulte, n=61%). Differences in FFP rates between favorable and unfavorable patients were significant only for GHSG criteria (p=0.02) with there were no differences in OS rates for any criteria. Five of 6 patients who relapsed were successfully salvaged.The majority of our patients deemed unfavorable had an excellent outcome despite undergoing a significantly abbreviated regimen. Application of factors used by the GHSG defined a less favorable subset for FFP but with no impact on OS. As therapy for early-stage disease moves to further reductions in therapy, these factors take on added importance in the interpretation of current trial results and design of future studies.

Abstract

Total skin electron beam therapy (TSEBT) is a highly effective treatment for mycosis fungoides (MF). The standard course consists of 30 to 36 Gy delivered over an 8- to 10-week period. This regimen is time intensive and associated with significant treatment-related toxicities including erythema, desquamation, anhydrosis, alopecia, and xerosis. The aim of this study was to identify a lower dose alternative while retaining a favorable efficacy profile.One hundred two MF patients were identified who had been treated with an initial course of low-dose TSEBT (5-<30 Gy) between 1958 and 1995. Patients had a T stage classification of T2 (generalized patch/plaque, n = 51), T3 (tumor, n = 29), and T4 (erythrodermic, n = 22). Those with extracutaneous disease were excluded.Overall response (OR) rates (>50% improvement) were 90% among patients with T2 to T4 disease receiving 5 to <10 Gy (n = 19). In comparison, OR rates between the 10 to <20 Gy and 20 to <30 Gy subgroups were 98% and 97%, respectively. There was no significant difference in median progression free survival (PFS) in T2 and T3 patients when stratified by dose group, and PFS in each was comparable to that of the standard dose.OR rates associated with low-dose TSEBT in the ranges of 10 to <20 Gy and 20 to <30 Gy are comparable to that of the standard dose (? 30 Gy). Efficacy measures including OS, PFS, and RFS are also favorable. Given that the efficacy profile is similar between 10 and <20 Gy and 20 and <30 Gy, the utility of TSEBT within the lower dose range of 10 to <20 Gy merits further investigation, especially in the context of combined modality treatment.

Abstract

Combining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors.We treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and-at that same site-injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells.This in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response.In situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.

Abstract

A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.

Abstract

Although the new World Health Organization-European Organization for Research and Treatment of Cancer classification focuses on providing uniformity in the diagnosis of cutaneous lymphomas, cutaneous peripheral T-cell lymphoma (PTL) remains a poorly defined subgroup. As follow-up to a study of systemic PTL complicated by a proliferation of B cells, we studied 16 cases of cutaneous PTL that contained morphologically atypical T cells associated with a significant infiltrate of B cells (about 20%-50%). A clonal T-cell receptor gamma chain gene rearrangement was present in all cases. In contrast, a clonal immunoglobulin heavy chain gene rearrangement was present in only 1 case. Clinical staging in 14 cases identified systemic involvement in 2. At last follow-up, both patients with systemic involvement had died of disease, and the majority of patients with primary cutaneous disease were alive (11/12). The presence of numerous atypical B cells and T cells caused diagnostic confusion in these cases. Comprehensive pathologic studies, coupled with clinical staging, are necessary for the accurate diagnosis of this unusual manifestation of cutaneous PTL.

Abstract

In almost half of patients diagnosed with Hodgkin's disease (HD), the malignant Reed-Sternberg (RS) cells express Epstein-Barr virus (EBV) antigens. Multiple translational efforts are actively investigating antitumor immune strategies by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. In an effort to explore the EBV-specific immune response, here we characterize EBV-specific CTL responses to lytic and latent EBV antigens in 12 consecutive EBV carriers with EBV-negative HD. Compared to healthy donors, we detected weak, baseline EBV-specific responses to both lytic and latent antigens by IFN-gamma ELISPOT in patients with EBV-negative HD at diagnosis. Chemoradiotherapy was associated temporally with a decrease EBV-specific responses. At final follow-up (24 months), recovery of EBV-specific CTL responses was observed with robustness of lytic-specific response equivalent to healthy controls. We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment. Our observation challenges prior belief that patients with HD remain immunodeficient following therapy and argues that the clinical significance of the EBV-specific immune response in EBV-negative HD should be further investigated.

Abstract

Optimal treatment of indolent primary cutaneous B-cell lymphoma (CBCL), marginal zone lymphoma, and follicle center lymphoma, presenting as multiple lesions, has yet to be established. Rituximab is a chimeric monoclonal IgG1 antibody directed against the CD20 antigen of B cells. Clinical efficacy of systemic rituximab in CBCL has yet to be established.We sought to assess the efficacy of systemic rituximab in the treatment of CBCL.This was a retrospective study of 15 patients with indolent CBCL treated with intravenous rituximab (375 mg/m(2)) as a single agent. Variable maintenance regimen was used in a subset of patients. Responses were categorized as complete response, partial response, stable disease, or progressive disease. The efficacy end points included were objective response rate, time to response, time to progression, and duration of response.Ten patients with follicle center lymphoma and 5 with marginal zone lymphoma were included. The objective response rate was 87% (60% complete response, 27% partial response). All patients with follicle center lymphoma had a response with 80% achieving complete response. Of the patients with marginal zone lymphoma, 3 had a response, one stable disease, and one progressive disease. Median follow-up was 36 months. Median time to response, duration of response, and time to progression was 30 days, 24 months, and 24 months, respectively.The study was limited by the small sample size and retrospective design.This study, although small, suggests that rituximab is a reasonable first-line treatment option for indolent CBCL with multiple lesions where local treatment is not effective or desirable.

Abstract

Woringer-Kolopp disease, also known as pagetoid reticulosis, is an exceedingly rare variant of mycosis fungoides. Accurate diagnosis and effective treatment is essential to prevent progression to debilitating disease. We identified 7 patients with Woringer-Kolopp disease treated at our institution. We review the major clinical and pathologic characteristics of this disease, focusing on treatment strategies and patient outcomes. All of our patients were successfully treated with skin-directed therapies including topical steroids, topical nitrogen mustard, psoralen plus ultraviolet A, narrow-band ultraviolet B, and radiation therapy. Our observations confirm that Woringer-Kolopp disease carries an excellent prognosis, and support that the most effective and appropriate treatment for recalcitrant or severe Woringer-Kolopp disease is localized radiation therapy.

Abstract

We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donor's hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.

Hodgkin's lymphoma: The role of radiation in the modern combined strategies of treatmentHEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICAHoppe, R. T.2007; 21 (5): 915-?

Abstract

A history of the treatment of Hodgkin's disease with radiation therapy and chemotherapy is presented. Studies are reviewed examining treatment for favorable and unfavorable presentation of stage I-II disease, stage III-IV disease, and relapsed disease. In this era of combined-modality therapy we have reached the point of near-total conquest of Hodgkin's lymphoma, but challenges remain. Directions for future research are discussed.

Abstract

To correlate [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen.We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [(18)F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans.After chemotherapy, six of 81 patients had residual [(18)F]FDG-PET-positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [(18)F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [(18)F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [(18)F]FDG-PET-negative patients versus 33% in [(18)F]FDG-PET-positive patients (P < .0003). In a bivariate Cox model, [(18)F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2.These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.

TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC)BLOODKim, Y. H., Willemze, R., Pimpinelli, N., Whittaker, S., Olsens, E. A., Ranki, A., Dummer, R., Hoppe, R. T.2007; 110 (2): 479-484

Abstract

Currently availabel staging systems for non-Hodgkin lymphomas are not useful for clinical staging classification of most primary cutaneous lymphomas. The tumor, node, metastases (TNM) system used for mycosis fungoides (MF) and Sézary syndrome (SS) is not appropriate for other primary cutaneous lymphomas. A usable, unified staging system would improve the communication about the state of disease, selection of appropriate management, standardization of enrollment/response criteria in clinical trials, and collection/analysis of prospective survival data. Toward this goal, during the recent meetings of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC), the representatives have established a consensus proposal of a TNM classification system applicable for all primary cutaneous lymphomas other than MF and SS. Due to the clinical and pathologic heterogeneity of the cutaneous lymphomas, the currently proposed TNM system is meant to be primarily an anatomic documentation of disease extent and not to be used as a prognostic guide.

Abstract

Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies.The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations.New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkin's and Hodgkin's lymphoma. Standardized definitions of end points are provided.We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.

Abstract

To assess risks for developing second malignancies in patients with mycosis fungoides or Sézary syndrome.Retrospective study of 2 cohorts.Nine population-based US cancer registries that constitute the Surveillance, Epidemiology, and End Results Program (SEER-9), and Stanford University referral center cohort of patients with cutaneous lymphoma. Patients with mycosis fungoides or Sézary syndrome from the SEER-9 registry diagnosed and followed up from 1984 through 2001 and from the Stanford University cohort diagnosed and followed up from 1973 through 2001.Relative risk was estimated using the standardized incidence ratio (SIR). The expected cancer incidence for both cohorts was calculated using age-, sex-, race-, and calendar year-specific SEER-9 incidence rates for the general population. Nonmelanoma skin cancers were excluded because these cancers are not routinely reported by the SEER database.In the SEER-9 cohort (n = 1798), there were 197 second instances of cancer (SIR = 1.32; 95% confidence interval [CI], 1.15-1.52) at all sites. Significantly elevated risk (P

Abstract

To evaluate the usefulness of integrated positron emission tomography and computed tomography (PET/CT) in staging mycosis fungoides (MF) and Sézary syndrome and to correlate PET/CT data with histopathologic diagnosis of lymph nodes (LNs).A single-center, prospective cohort analysis.Academic referral center for cutaneous lymphoma.Thirteen patients with MF and SS at risk for secondary LN involvement. Interventions Patients were clinically evaluated based on general physical examination, total body skin examination, and laboratory screening. They underwent integrated PET/CT followed by excisional biopsy of LNs.We used PET/CT to assess LN size and metabolic activity. Enlarged LNs were defined as axillary or inguinal LNs with a short axis 1.5 cm or larger; or cervical LN, with a short axis 1.0 cm or larger. We classified LN pathologic results according to National Cancer Institute (LN1-4) and World Health Organization (WHO 1-3) criteria. We quantified PET activity using standardized uptake value (SUV) and correlated with LN grade.Based on CT size criteria alone, only 5 patients had enlarged LNs, whereas PET revealed hypermetabolic LNs in all 13 patients. Six patients had LN1-3, and 7 had effacement of LN architecture by lymphoma cells (LN4). Of the 7 patients with LN4 nodes, 4 had SS, and 3 had tumorous MF. Two patients with LN4 nodes had inguinal LNs smaller than 1.5 cm and would have been assigned an N0 classification without the use of integrated PET/CT. Correlation of SUV with LN grade revealed that LN1-3 nodes were associated with a mean SUV of 2.7 (median SUV, 2.2; range, 2.0-4.7) and LN4 nodes were associated with a mean SUV of 5.4 (median SUV, 3.9; range, 2.1-11.8). Patients with large cell transformation had the highest SUVs.For staging MF and SS, PET/CT was more sensitive in detecting LN involved by lymphoma compared with CT data alone and thus may provide more accurate staging and prognostic information. The intensity of PET activity correlated with histologic LN grade.

Abstract

Conditioning with total lymphoid irradiation plus antithymocyte serum protects mice against acute graft-versus-host disease (GVHD) after hematopoietic-cell transplantation. We tested this strategy in humans.Thirty-seven patients with lymphoid malignant diseases or acute leukemia underwent an experimental conditioning regimen with 10 doses of total lymphoid irradiation (80 cGy each) plus antithymocyte globulin, followed by an infusion of HLA-matched peripheral-blood mononuclear cells from related or unrelated donors who received granulocyte colony-stimulating factor.Of the 37 transplant recipients, only 2 had acute GVHD after hematopoietic-cell transplantation. Potent antitumor effects in patients with lymphoid malignant diseases were shown by the change from partial to complete remission. In the transplant recipients who underwent conditioning with total lymphoid irradiation and antithymocyte globulin, the fraction of donor CD4+ T cells that produced interleukin-4 after in vitro stimulation increased by a factor of five, and the proliferative response to alloantigens in vitro was reduced, as compared with normal control subjects and control subjects who underwent conditioning with a single dose of total-body irradiation (200 cGy).A regimen of total lymphoid irradiation plus antithymocyte globulin decreases the incidence of acute GVHD and allows graft antitumor activity in patients with lymphoid malignant diseases or acute leukemia treated with hematopoietic-cell transplantation.

Abstract

Strategies to induce donor-specific allograft tolerance are best tested in preclinical models developed in nonhuman primates (NHPs). Most protocols prepare the recipient by infusing hematopoietic cells from the donor. We report here a procedure to isolate and characterize large numbers of bone marrow cells (BMCs) from cynomolgus monkeys (cynos) that can then successfully be transplanted into conditioned recipients.Vertebral columns of five cynos were excised en bloc and separated into individual vertebrae. The cancelous bone was extracted with a core puncher, fractionated, filtered, centrifuged, and resuspended in transplantation media before being analyzed by flow cytometry. In two instances, the collected BMCs were reinfused into allogeneic recipients preconditioned with a nonmyeloablative regimen. Chimerism was monitored using short-tandem repeat analysis.The mean total BMCs yield was 25.5 x 10(9) (range of 4.00 x 10(9) to 59 x 10(9)) with mean cell viability of 93.4% (range: 90-96%). CD34+ cells and CD3+ cells averaged 0.34 and 3.91% of total BMCs, respectively. This resulted in absolute cell number yields of 1.02 x 10(8) and 1.15 x 10(9) for CD34+ and CD3+ cells, respectively. Graft-versus-host disease was absent in both bone marrow infused animals, and a maximum level of chimerism of 18% was detected at 3 weeks after BMCs infusion.We present here the first detailed report of a procedure to retrieve and characterize large numbers of BMCs from vertebral bodies of cynos and demonstrate that cells collected with this technique have the capability of engrafting in allogenic recipients.

Abstract

Systemic B-cell lymphomas have been studied using microarrays, which has led to a better understanding of their molecular characteristics. Initial microarray studies of these lymphomas have implicated several genes as important predictors of outcome. In this study, we used a tissue microarray (TMA) to characterize primary cutaneous large B-cell lymphomas (PCLBCL).We studied 14 patients for whom clinical follow up was available, including four patients whose lesions were limited to the leg on presentation. Immunohistochemical staining with CD20, CD44, CD21, CD5, CD10, bcl-2, bcl-6, Ki67, p53, and multiple myeloma 1 (MUM1) was examined.Our results identify two subgroups of lymphomas. The first group showed staining with bcl-6 and had an overall survival of 176 months (p = 0.003). The majority of this group was negative for MUM1. The second group lacked staining with bcl-6 and had an overall survival of 26 months, with a majority of these cases staining with MUM1. Three of four patients with PCLBCL of the leg showed no staining with bcl-6.Our study demonstrates the utility of TMAs in the analysis of PCLBCL and that expression of bcl-6 and MUM1 correlates with survival.

Abstract

Chimerism assessment following bone marrow transplantation (BMT) in cynomolgus monkeys (cynos) has been hampered by the lack of good engraftment markers. In human BMT, such markers have been provided by short tandem repeat (STR) loci. We tested the idea that techniques effective for detecting human STR could be readily adapted to cynos. Genomic DNA was extracted from cyno unseparated blood or peripheral cell subsets. With only slight modifications, reagents for detecting human STR alleles were used to amplify and detect cyno STRs and to quantitate allelic mixtures on an automated sequencer. Of the 15 STR loci tested, only CSF1PO, D18S51, and FGA successfully amplified, with seven, seven and two alleles, respectively. CSF1PO and D18S51 heterozygosity (80% and 55%, respectively) allowed use of these two loci for chimerism quantitation after BMT. The successful adaptation of human STR reagents to monitor chimerism in transplanted cynos will facilitate the use of this species in preclinical tolerance studies.

Abstract

Posttransplantation lymphoproliferative disorders (PTLDs) are lymphoid proliferations that can develop in recipients of solid organ or allogeneic bone marrow transplants. They are clinically and pathologically heterogeneous and range from polyclonal hyperplastic lesions to malignant lymphomas. Although extranodal involvement in PTLD is common, cutaneous presentation is rare, with only 19 cases reported previously.We describe 4 patients with cutaneous presentations of PTLD. All patients had relatively late-onset PTLD (>1 year after transplantation) with a median of 8 years from organ allograft to tumor diagnosis. The extent, number, and anatomic location of skin lesions varied from a localized patch to widespread nodules. None of the patients exhibited systemic symptoms at the time of PTLD diagnosis. Pathological findings ranged from plasmacytic hyperplasia to monomorphic PTLD. In situ hybridization detected Epstein-Barr virus messenger RNA in all 3 cases with evaluable tissue. All patients underwent reduction in immunosuppressive therapy and received other individualized treatments. Median follow-up was 2.5 years. At the most recent follow-up, 3 patients were in complete remission and 1 had residual disease.In this study, PTLD lesions presenting in the skin responded to therapy. Despite their relatively late occurrence after transplantation, most of these cases were positive for Epstein-Barr virus. As observed with other cutaneous lymphomas, the PTLDs with predominant skin involvement had a relatively favorable outcome.

Abstract

To review our experience managing extranodal nonorbital indolent lymphomas of the head and neck.A retrospective review was made of 40 patients with indolent lymphomas of the head and neck evaluated at Stanford. The tumor head-and-neck location was Waldeyer's ring, 14; salivary glands, 16; thyroid, 4; and other sites, 6. Twenty-five were Stage I-IIE. Pathology was re-reviewed in 37. The most common histologies were marginal zone lymphoma and follicular grade 2. Patients received combinations of surgery, chemotherapy, and radiotherapy. Local therapy included surgery alone in 6 patients, radiotherapy alone in 7, and surgery plus radiotherapy in 12. Median follow-up was 70.5 months.Freedom from local progression was 86%, and freedom from progression was 61% at 5 years. Patients with radiotherapy had significantly better freedom from local progression (5-year, 100% vs. 72% for patients without radiotherapy, p = 0.006) and freedom from progression (5-year, 90% vs. 34% for patients without radiotherapy, p = 0.001). Improvement in freedom from progression with radiotherapy was statistically significant for Stage I-II patients (88% vs. 50%, p = 0.02) and of borderline significance in Stage III-IV patients (100% vs. 23%, p = 0.07). Overall survival at 10 years was 70%. Multivariate analysis revealed that significant prognostic factors for survival were tumor site (favoring salivary and thyroid, p = 0.02) and age (favoring younger, p = 0.04).Survival is excellent in patients with indolent lymphomas of the head and neck. Patients with salivary and thyroid primary tumors had better survival compared with others. Early use of radiotherapy resulted in significantly higher rates of freedom from progression and freedom from local progression in early-stage patients.

Abstract

CD30+ cutaneous lymphoproliferative disorders (CLPDs) include lymphomatoid papulosis, borderline cases of CD30+CLPDs, and primary cutaneous anaplastic large cell lymphoma (PCALCL). Prior studies have shown CD30+CLPDs have an excellent prognosis.We sought to present the single-center experience of Stanford University, Stanford, Calif, in the management of CD30+CLPDs.A retrospective cohort analysis of 56 patients with CD30+CLPDs treated at our institution was performed.No patients with lymphomatoid papulosis died of disease, and overall survival was 92% at 5 and 10 years. Disease-specific survivals at 5 and 10 years for PCALCL were 85%. Disease-specific survival at 5 years for localized versus generalized PCALCL was 91% versus 50% (P =.31). PCALCL was highly responsive to treatment, but the relapse rate was 42%. In all, 3 patients progressed to extracutaneous stage of disease. No clinical or histologic factors analyzed were predictive of worse outcome in lymphomatoid papulosis and PCALCL.Similar to prior reports from multicenter European groups, the single-center experience at our institution demonstrates CD30+CLPDs have an overall excellent prognosis; however, cases of PCALCL with poor outcome do exist.

Abstract

To study and update the clinical characteristics and long-term outcome of our patients with mycosis fungoides (MF) and Sézary syndrome (SS), and to identify important clinical factors predictive of survival and disease progression.A single-center, retrospective cohort analysis.Academic referral center for cutaneous lymphoma.Five hundred twenty-five patients with MF and SS evaluated and managed at Stanford University Cutaneous Lymphoma Clinic, Stanford, Calif, from 1958 through 1999.We calculated long-term actuarial overall and disease-specific survivals and disease progression by the Kaplan-Meier method, and relative risk (RR) for survival calculated from expected survivals in control populations.The majority of our patients presented with T1 (30%) or T2 (37%) disease; 18% presented with T3 and 15% with T4 skin involvement. Forty-three percent of deaths were attributable to MF, primarily in patients with T3 or T4 disease. The patients with a more advanced T classification and clinical stage had a worse survival outcome. Except for patients with T1 or stage IA disease, the RR for death is greater in patients with MF than in a control population (RR, 2.2 in stage IB/IIA disease, 3.9 in stage IIB/III disease, and 12.8 in stage IV disease). Despite similar overall survival in patients with stage IB or IIA disease, their disease-specific survivals were significantly different (P =.006). The most significant clinical prognostic factors in the univariate analysis were patient age, TNM and B classifications, overall clinical stage groupings, and the presence or absence of extracutaneous disease. In the multivariate analysis, patient age, T classification, and the presence of extracutaneous disease were the most important independent factors. The risk for disease progression to a more advanced TNM or B classification, worse clinical stage, or death due to MF correlated with the severity of the initial T classification. The risk for development of extracutaneous disease also correlated with T classification; none of these patients had T1 disease when their extracutaneous disease was detected.Patients with MF and SS have varying risks for disease progression or death. The most important clinical predictive factors for survival include patient age, T classification, and the presence of extracutaneous disease. The significant disease-specific survival differences between different clinical stages validate the usefulness of the present MF clinical staging system of the National Cancer Institute.

Abstract

Lymphocyte-predominant Hodgkin disease (LPHD) is a unique clinical entity characterized by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy. The malignant cells of LPHD are CD20+ and therefore rituximab may have activity with fewer late effects than standard therapy. In this phase 2 trial, 22 patients with CD20+ LPHD received 4 weekly doses of rituximab at 375 mg/m2. Ten patients had previously been treated for Hodgkin disease, while 12 patients had untreated disease. All 22 patients responded to rituximab (overall response rate, 100%) with complete response (CR) in 9 (41%), unconfirmed complete response in 1 (5%), and partial response in 12 (54%). Acute treatment-related adverse events were minimal. With a median follow-up of 13 months, 9 patients had relapsed, and estimated median freedom from progression was 10.2 months. Progressive disease was biopsied in 5 patients: 3 had recurrent LPHD, while 2 patients had transformation to large-cell non-Hodgkin lymphoma (LCL). All 3 patients with recurrent LPHD were retreated with rituximab, with a second CR seen in 1 patient and stable disease in 2. Rituximab induced prompt tumor reduction in each of 22 LPHD patients with minimal acute toxicity; however, based on the relatively short response duration seen in our trial and the concerns about transformation, rituximab should be considered investigational treatment for LPHD. Further clinical trials are warranted to determine the optimal dosing schedule of rituximab, the potential for combination treatment, and the possible relationship of rituximab treatment to the development of LCL.

Abstract

We studied gene expression profiles of 17 cutaneous B cell lymphomas that were collected with 4-6 mm skin punch biopsies. We also included tissue from two cases of mycosis fungoides, three normal skin biopsies, and three tonsils to create a framework for further interpretation. A hierarchical cluster algorithm was applied for data analysis. Our results indicate that small amounts of skin tissue can be used successfully to perform microarray analysis and result in distinct gene expression patterns. Duplicate specimens clustered together demonstrating a reproducible technique. Within the cutaneous B cell lymphoma specimens two specific B cell differentiation stage signatures of germinal center B cells and plasma cells could be identified. Primary cutaneous follicular and primary cutaneous diffuse large B cell lymphomas had a germinal center B cell signature, whereas a subset of marginal zone lymphomas demonstrated a plasma cell signature. Primary and secondary follicular B cell lymphoma of the skin were closely related, despite previously reported genetic and phenotypic differences. In contrast primary and secondary cutaneous diffuse large B cell lymphoma were less related to each other. This pilot study allows a first glance into the complex and unique microenvironment of B cell lymphomas of the skin and provides a basis for future studies, which may lead to the identification of potential histologic and prognostic markers as well as therapeutic targets.

Abstract

To evaluate and update the response and survival outcomes and toxic effects in patients treated with topical nitrogen mustard (mechlorethamine hydrochloride) as primary therapy.A single-center, retrospective cohort analysis.Academic referral center for cutaneous lymphoma.A total of 203 patients with mycosis fungoides (clinical stages I-III) treated with topical nitrogen mustard as initial therapy.Long-term actuarial survival, freedom-from-relapse, and freedom-from-progression results as calculated by the Kaplan-Meier method.The overall response rate for the 203 patients was 83%, with a complete response rate of 50%. The median time to achieve complete response was 12 months (T1, 10 months; T2, 19 months), and the median time to relapse was 12 months. The duration of complete response increased with longer maintenance therapy; however, after completion of therapy, the response duration or relapse rate was similar regardless of maintenance regimen. Patients with T1 disease had better response and survival outcomes than those with T2 disease, with overall and complete response rates in T1 of 93% and 65%, respectively, and in T2, 72% and 34%, respectively. A similar clinical response was seen for patients with stage IIA vs IB. Sixty-eight percent of 203 patients received only topical nitrogen mustard therapy throughout their follow-up course, including most of the patients who achieved an initial complete response. The clinical response to topical nitrogen mustard as salvage therapy was similar to initial response rates. The efficacy results were similar in patients treated with aqueous vs ointment preparations. Freedom-from-progression rates in T1 disease (no progression to higher T classification or worse clinical stage) at 5 and 10 years were 92% and 85%, respectively, and in T2, 83% at 5 and 10 years. Fewer than 10% of patients experienced contact hypersensitivity reactions when topical nitrogen mustard was used as an ointment preparation. Only 8 patients (4%) developed secondary cutaneous malignancy, none attributable to topical nitrogen mustard monotherapy. Pediatric patients experienced no significant toxic effects with topical nitrogen mustard therapy.Topical nitrogen mustard remains an effective primary initial or salvage therapy in mycosis fungoides for patients with T1 and T2 disease. Long-term follow-up results confirm its safety.

Abstract

Radiation therapy is the most effective single agent for the treatment of mycosis fungoides. There are well-defined dose-response relationships for achieving a complete response as well as the durability of this response. Techniques of electron beam therapy have been developed that permit treatment of the entire skin. Total-skin electron beam therapy is an important form of management, especially for patients who have thick generalized plaque or tumorous disease. Radiation therapy may also be used selectively for treatment of extracutaneous disease.

Abstract

Total lymphoid irradiation (TLI) is used to treat recurrent allograft rejection. Short-term success and complication rates have been reported in pediatric and adult cardiac transplant populations. We report the long-term efficacy and safety of TLI in treating intractable rejection in pediatric patients.Eight pediatric patients were treated with TLI (7 for recurrent rejection, 1 for risk of medication non-compliance). Therapy consisted of a mid-plane dose of 8 Gy administered with a 6-MeV linear accelerator using an anterior-posterior opposed technique. We reviewed outcomes for a total of 40 patient-years of follow-up.We encountered rejection (>Grade 2 by International Society for Heart and Lung Transplantation criteria) in 56.7% +/- 34.7% of biopsies performed within 90 days before TLI. Rejection rates dropped to 3.1% +/- 8.8% within the first 90 days (p < 0.005) after therapy and remained low at 5.6% +/- 1.3% (p < 0.05) during the first year after completion of TLI. Median time from TLI to the first subsequent rejection episode was 305 days (range, 77-1,920 days). Long-term follow-up (>3 years) of 5 patients demonstrated a continuing low incidence of rejection. Non-Hodgkin's lymphoma was diagnosed in 1 of 8 patients, graft coronary artery disease in 4 of 8 patients, and restrictive cardiomyopathy in 1 of 8 patients after TLI.Total lymphoid irradiation is an effective treatment for recurrent rejection and has short- and long-term efficacy. Morbid events may include cancer, graft coronary artery disease, and restrictive cardiomyopathy.

Abstract

Rodents and dogs conditioned with total-lymphoid irradiation (TLI), with or without antithymocyte globulin (ATG), have been shown to develop mixed chimerism and immune tolerance without graft-versus-host disease (GVHD) after the infusion of major histocompatability complex (MHC)-mismatched donor bone marrow cells given alone or in combination with an organ allograft.Four human leukocyte antigen (HLA)-mismatched recipients of living donor kidney transplants were conditioned with TLI and ATG posttransplantation and infused with cyropreserved donor granulocyte colony-stimulating factor (G-CSF) "mobilized" hematopoietic progenitor (CD34+) cells (3-5x10(6) cells/kg) thereafter. Maintenance prednisone and cyclosporine dosages were tapered, and recipients were monitored for chimerism, GVHD, graft function, T-cell subsets in the blood, and antidonor reactivity in the mixed leukocyte reaction (MLR).Three of the four patients achieved multilineage macrochimerism, with up to 16% of donor-type cells among blood mononuclear cells without evidence of GVHD. Prolonged depletion of CD4+ T cells was observed in all four patients. Rejection episodes were not observed in the three macrochimeric recipients, and immunosuppressive drugs were withdrawn in the first patient by 12 months. Prednisone was withdrawn from a second patient at 9 months, and cyclosporine was tapered thereafter.Multilineage macrochimerism can be achieved without GVHD in HLA-mismatched recipients of combined kidney and hematopoietic progenitor transplants. Conditioning of the host with posttransplant TLI and ATG was nonmyeloablative and was not associated with severe infections. Recipients continue to be studied for the development of immune tolerance.

Abstract

To define the natural history, prognosis, and radiocurability of localized orbital extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT).Clinical records and pathologic material of 40 patients treated with local radiotherapy for localized orbital lymphoma were reviewed. Treatment consisted of 30-40 Gy in 1.8-2-Gy fractions (mean 34 Gy) of irradiation using 9-20-MeV electrons for conjunctival lesions, or 6-MV photons with complex treatment planning for retrobulbar lesions. The lens was routinely shielded with the use of a suspended eye bar.Upon pathologic review, 31 cases of orbital MALT lymphoma were identified. With the median follow-up of 5.9 years (range 9 months-0.3 years), the actuarial 10-year overall survival was 73%. Local control was 100%. Five distant failures resulted in a projected 10-year freedom from relapse of 71%. Most of the failures were extranodal in sites where MALT lymphoma has previously been shown to arise. No difference in outcome was observed among patients treated to less than or equal to 34 Gy vs. those treated to higher radiation doses. Two patients experienced clinically significant retinal damage after doses > or = Gy.In this study, localized orbital MALT lymphoma was well controlled with radiotherapy. Even following relapse, patients with orbital MALT lymphoma exhibited an indolent course. Relapse occurred predominantly in extranodal mucosal sites, implying a possible homing mechanism for MALT lymphoma cells. Given the excellent local control rates, our current treatment recommendation is to use a radiation dose of 30-30.6 Gy in 1.5-.8-Gy fractions to minimize risk of late toxicity.

Abstract

To provide more mature data on the efficacy and complications of a brief, dose-intense chemotherapy regimen plus radiation therapy (RT) to bulky disease sites for locally extensive and advanced-stage Hodgkin's disease.One hundred forty-two patients with stage III or IV or locally extensive mediastinal stage I or II Hodgkin's disease received Stanford V chemotherapy for 12 weeks followed by 36-Gy RT to initial sites of bulky (> or =5 cm) or macroscopic splenic disease. Freedom from progression (FFP), overall survival (OS), and freedom from second relapse (FF2R) were determined using life-table estimates. Outcomes were analyzed according to the international prognostic score. Late effects of treatment were recorded in follow-up.With a median follow-up of 5.4 years, the 5-year FFP was 89% and the OS was 96%. No patient progressed during treatment, and there were no treatment-related deaths. FFP was significantly superior among patients with a prognostic score of 0 to 2 compared with those with a score of 3 and higher (94% v 75%, P

Abstract

To describe and identify the clinical and pathologic features of prognostic significance for natural killer (NK) and NK-like T-cell (NK/T-cell) lymphoma presenting in the skin.This study was a retrospective review of 30 patients with CD56+ lymphomas initially presenting with cutaneous lesions, with analysis of clinical and histopathologic parameters.The median survival for all patients was 15 months. Those with extracutaneous manifestations at presentation (11 patients) had a shorter median survival of 7.6 months as compared with those without extracutaneous involvement (17 patients), who had a more favorable median survival of 44.9 months (P =.0001). Age, gender, extent of cutaneous involvement, and initial response to therapy had no statistically significant effect on survival. Seven patients (24%) had detectable Epstein-Barr virus (EBV) within neoplastic cells. The patients with tumor cells that coexpress CD30 (seven patients) have not yet reached a median survival after 35 months of follow-up as compared with those with CD30- tumor cells (20 patients), who had a median survival of 9.6 months (P

Abstract

To identify prognostic factors predictive of outcome in patients with extracutaneous (stage IV) mycosis fungoides (MF) and to evaluate the risk of progression to extracutaneous disease by initial extent of skin involvement.One hundred twelve patients with extracutaneous disease at presentation or with progression and 434 patients with initial cutaneous-only disease were identified. Actuarial survival curves were plotted according to the Kaplan-Meier technique.The median survival of all stage IV patients was 13 months from the date of first treatment for stage IV disease. Sex, race, age, extent of skin involvement, and peripheral blood Sezary cell involvement were not significant to survival outcome. Eleven patients (10%) had a complete response to therapy resulting in a significantly improved median survival compared with patients with a partial or no response (1.70 v 0.91 years, P =.047 and 1.70 v 0.57 years, P =.011, respectively). At 20 years from diagnosis, the risk for progression to extracutaneous disease by initial extent of skin involvement was 0% for limited patch/plaque, 10% for generalized patch/plaque, 35.5% for tumorous disease, and 41% for erythrodermic involvement.This was a larger scale study over a longer time period than had been completed previously on extracutaneous MF. Prognostic factors important in the cutaneous stages of disease are no longer significant once extracutaneous disease develops. Patients who had a more favorable response to therapy may have had a biologically less aggressive disease than their less fortunate counterparts. The risk of developing stage IV MF is highest in patients presenting with tumorous or erythrodermic skin disease and is lowest in patients with limited skin involvement.

Abstract

Advanced stage follicular small cleaved and mixed cell lymphoma is characterized by relapse from remission and survival ranging from 6 to 12 years. Because young patients have the greatest compromise in longevity, the efficacy and toxicity of high-dose radiochemotherapy and bone marrow transplantation after conventional chemotherapy was evaluated in a prospective phase II clinical trial. Thirty-seven patients in a minimal disease state after conventional chemotherapy received fractionated total body irradiation and high-dose etoposide and cyclophosphamide, followed by purged autologous bone marrow. A reference sample of 188 patients of similar age, stage, and histology managed at this institution before 1988 was identified for comparison of patient characteristics and outcomes. Compared with reference patients, transplant recipients had a higher tumor burden at diagnosis. With a median follow-up of 6.5 years, the estimated 10-year survival after transplantation was 86%. There was a single lymphoma death yielding a 10-year disease-specific survival of 97%. There were 2 early transplant-related deaths and 2 late acute leukemia deaths. Ten patients relapsed, one with microscopic disease only. High tumor burden at diagnosis and incomplete response to chemotherapy adversely influenced survival in the reference but not in the transplanted patients. The estimated risk of death of 14% and relapse of 30% at 10 years in our transplanted follicular lymphoma patients, the majority of whom had high tumor burdens, compares favorably with our observations in appropriately matched reference patients.

Abstract

A retrospective analysis was performed to investigate the outcome of high-dose therapy (HDT) and autologous hematopoietic cell transplantation in patients with follicular lymphomas beyond first remission. Ninety-two patients with primary induction failure or relapsed follicular low-grade lymphoma (FLGL), follicular large cell lymphoma (FLCL), and transformed follicular lymphoma (TFL) were treated with myeloablative therapy consisting of etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and either carmustine (BCNU;15 mg/kg) or fractionated total body irradiation (FTBI; 1200 cGy) followed by transplantation of purged autologous bone marrow or peripheral blood hematopoietic cells. For the 49 patients with relapsed FLGL, the median age was 49 years and the median interval from diagnosis to HDT was 30 months. The 4-year estimate of overall survival (OS) was 60% (95% confidence interval [CI], 45%-75%) and of disease-free survival (DFS) was 44% (95% CI, 29%-59%). Treatment with the FTBI-containing HDT regimen was associated with significantly longer DFS (P = .04) and OS (P = .04) in our multivariate analysis. OS was also significantly longer among those treated with 3 or fewer chemotherapy regimens. For the 26 FLCL patients, the median age was 51 years and in 31% the indication for HDT was primary induction failure. For FLCL patients, the 4-year estimate of OS was 58% (95% CI, 37%-79%) and of DFS was 51% (95% CI, 30%-72%). Among the 17 patients with TFL, 13 (76%) transformed at first relapse, and only 6 patients (35%) achieved complete remission with salvage therapy prior to HDT. For TFL patients, the 4-year estimate of OS was 50% (95% CI, 24%-76%) and of DFS 49% (95% CI, 20%-78%). There were 3 occurrences of myelodysplasia (1 after treatment with TBI, 2 after BCNU treatment), yielding an estimated incidence of 7% (95% CI, 0%-16%) at 56 months. This analysis shows that relapsed FLGL patients treated with 3 or fewer different chemotherapy regimens show inferior survival. The HDT regimen containing FTBI appears to be superior to the BCNU-based regimen for relapsed FLGL, although longer follow-up is needed to evaluate late effects. Lastly, patients with TFL or induction failure and relapsed FLCL can achieve survival outcome comparable to those observed with the indolent follicular lymphomas.

Abstract

To report the long-term survival and late toxicity data of Stage III follicular lymphoma patients treated with primary radiotherapy.Sixty-six patients with Stage III follicular small cleaved (FSC) or follicular mixed (FM) non-Hodgkin's lymphoma were treated with total lymphoid irradiation (61 patients) or whole body irradiation (5 patients) as their primary treatment modality from 1963 to 1982 at Stanford University. Adjuvant chemotherapy was given to 13 patients.Median follow-up was 9.5 years with a range of 0.5-24.3 years. Median overall survival, cause-specific survival, freedom from relapse, and event-free survival were 9.5, 18.9, 7.1, and 5.1 years, respectively. Few initial relapses or lymphoma-related deaths were seen beyond the first decade of follow-up. Patient age and number of disease sites were the two strongest predictors of overall survival. The cohort of patients with limited Stage III disease demonstrated an 88% freedom from relapse and a 100% cause-specific survival with up to 23.5 years follow-up.The long-term survival data for Stage III FSC or FM non-Hodgkin's lymphoma treated with primary radiotherapy are at least comparable and possibly better than results achieved with other therapeutic approaches. Patients with limited Stage III disease do particularly well. Whether these results are superior to an initial approach of deferred therapy until clinically indicated is currently unknown.

Abstract

This study was performed, in a multi-institutional setting, to evaluate the efficacy and feasibility of the Stanford V chemotherapy regimen plus radiotherapy to bulky Hodgkin's disease sites.A two-stage design was implemented in a phase II study involving 47 patients with bulky mediastinal stage I/II or stage III/IV Hodgkin's disease. Twelve weeks of the Stanford V chemotherapy regimen were given with consolidative radiotherapy (36 Gy) to lymph nodes >/= 5 cm and/or macroscopic splenic disease. Treatment was administered in one of five institutions participating in the Eastern Cooperative Oncology Group.With a median follow-up of 4.8 years, 45 patients are alive and 40 have been continuously disease-free. The estimated freedom from progression was 87% at 2 years and 85% at 5 years. Overall survival was 96% at 2 and 5 years. There was one death from Hodgkin's disease and one death from an M5 acute leukemia. Six of seven relapsed patients received high-dose therapy and autologous stem-cell transplantation. The freedom from second progression for the seven relapsed patients was estimated at 98% at 3 years.Stanford V chemotherapy and consolidative radiotherapy to bulky disease is effective in bulky and advanced Hodgkin's disease in a multi-institutional setting. On this basis, an Intergroup study comparing doxorubicin, bleomycin, vinblastine, and dacarbazine with the Stanford V regimen has been initiated.

Abstract

To evaluate the incidence, detection, pathology, management, and prognosis of breast cancer occurring after Hodgkin's disease.Seventy-one cases of breast cancer in 65 survivors of Hodgkin's disease were analyzed.The median age at diagnosis was 24.6 years for Hodgkin's disease and 42.6 years for breast cancer. The relative risk for invasive breast cancer after Hodgkin's disease was 4.7 (95% confidence interval, 3.4 to 6. 0) compared with an age-matched cohort. Cancers were detected by self-examination (63%), mammography (30%), and physician exam (7%). The histologic distribution paralleled that reported in the general population (85% ductal histology) as did other features (27% positive axillary lymph nodes, 63% positive estrogen receptors, and 25% family history). Although 87% of tumors were less than 4 cm, 95% were managed with mastectomy because of prior radiation. Two women underwent lumpectomy with breast irradiation. One of these patients developed tissue necrosis in the region of overlap with the prior mantle field. The incidence of bilateral breast cancer was 10%. Adjuvant systemic therapy was well tolerated; doxorubicin was used infrequently. Ten-year disease-specific survival was as follows: in-situ disease, 100%; stage I, 88%; stage II, 55%; stage III, 60%; and stage IV, zero.The risk of breast cancer is increased after Hodgkin's disease. Screening has been successful in detecting early-stage cancers. Pathologic features and prognosis are similar to that reported in the general population. Repeat irradiation of the breast can lead to tissue necrosis, and thus, mastectomy remains the standard of care in most cases.

Abstract

The purpose of this review is to summarize the Stanford experience in Hodgkin's disease, the late effects of treatment, and strategies to improve management to maximize cure and decrease late effects in these patients.Between 1960 and 1999, 2617 consecutive patients with Hodgkin's disease have been seen, treated, and rigorously followed at Stanford. This population includes patients of all ages and stages of disease. The database summarizing this experience serves as the source of survival and mortality data over 4 decades. Two thousand two hundred thirty-two of the population comprise the group evaluated for secondary cardiac disease. Two thousand one hundred sixty-two patients have been evaluated for risk of secondary leukemia, non-Hodgkin's lymphoma, and solid tumors. Eight hundred eighty-five women were evaluated for secondary breast cancer, prompting a subsequent analysis of risk of secondary cancer among 694 pediatric patients.The probability of cure of Hodgkin's disease has dramatically improved over the past 40 years. Today, 94% of patients are expected to survive. Among those who do not survive, approximately half die of Hodgkin's disease, 20% of new cancers, and 14% of cardiovascular complications. Modifications in patient management and treatment have greatly reduced the serious late effects observed from prior therapy. With current combined-modality therapy using moderate doses of involved field of radiation and limited cycles of multiagent, risk adapted chemotherapy, serious cardiac complications and development of secondary cancers are expected to be greatly reduced. The Stanford 25-year pediatric Hodgkin's disease experience reveals that survival in favorable early-stage disease exceeds 95%. Newer protocols for children with advanced-stage disease continue to show these excellent survival rates and promise less late morbidity. Adult protocols using the risk-adapted Stanford V combined-modality program now parallel the pediatric experience, with greater than 90% survival in these patients.Thus today the likelihood of cure of Hodgkin's disease greatly exceeds the risk of late effects, a goal both Dr. Henry Janeway and Madame Marie Curie emphasized and taught from first-hand experience.

Abstract

The purpose of this study was to differentiate the patterns of nasal fossa involvement in nasopharyngeal carcinoma (NPC) and to clarify its prognostic influence on local control and survival after radiation therapy.Between November 1989 and July 1991, 218 patients with histologically proven local-regional NPC were treated with radiotherapy following the protocol at the Department of Radiation Oncology, Cancer Hospital, Shantou University School of Medicine. All patients had pretreatment CT scans. Fiberoptic endoscopic examination was performed every week during treatment and at the time of every follow-up visit to define the initial extent of disease and to evaluate treatment response. No chemotherapy or brachytherapy was given.Of the 218 patients, 87 had nasal involvement. Sixty of them had a pattern of mucosal infiltration (MI), another 27 had an exophytic protruding (EP) component. The likelihood of residual disease after irradiation, the local relapse rate, 5-year freedom from progression rate (FFP), and death rate associated with local relapse (DRALR) of MI and EP were 36.7% vs. 3.7%, 30.0% vs. 7.4%, 26.7% vs. 51.8%, and 25.0% vs. 3.7% with p<0.004, p<0.005, p<0.02, and p<0.03, respectively. Multivariate analysis in this selected group demonstrated that infiltration of nasal fossa mucosa was an independent prognostic factor on primary control and freedom from progression.Differentiation of nasal fossa involvement according to MI or EP is of value in predicting the outcome of treatment. We suggest that only the MI group should be considered as nasal involvement in the staging of NPC.

Abstract

Cutaneous involvement by B-cell lymphoma is often secondary to systemic disease. Primary cutaneous B-cell lymphomas are less common, and patients generally have an excellent prognosis. We present a patient with cutaneous B-cell lymphoma with clinical and histologic features mimicking mycosis fungoides. Although the patient was initially misdiagnosed as having a T-cell lymphoma, immunophenotypic studies demonstrated that this was a B-cell lymphoma.

Abstract

Mycosis fungoides (MF) and the Sézary syndrome are a group of extranodal non-Hodgkin's lymphomas of T-cell origin with primary cutaneous involvement. The group distinguishes itself from other primary cutaneous T-cell lymphomas (CTCLs) by its unique clinical features and histopathology. In its early stages, it often resembles common benign dermatoses, and therefore, a definitive diagnosis can be delayed. The affected T cells are characterized by a predominant CD4+ phenotype with frequent loss of CD7 (pan-T-cell antigen) and often demonstrate T-cell receptor (TCR) rearrangement. The prognosis of patients with MF is highly dependent on the extent and type of skin involvement. The initial cutaneous presentation of MF can be patches, plaques, tumors, or erythroderma. Patients who present with limited patch/plaque disease have an outstanding prognosis with an overall long-term survival that is similar to the expected survival of a matched control population. It is exceedingly rare for patients who present with limited or generalized patch/plaque disease without peripheral lymphadenopathy to have extracutaneous involvement. Therefore, the staging evaluation differs for patients with MF versus patients with other non-Hodgkin's lymphomas and should be tailored to the clinical presentation. Patients who have tumorous or erythrodermic skin involvement have a less favorable prognosis, and patients who present with extracutaneous disease have a poor prognosis. There are multiple therapeutic options for patients with MF and the Sézary syndrome. Selection of a specific treatment plan is based primarily on the clinical stage of the disease. The primary therapy for patients with patch/plaque disease without extracutaneous involvement is a topical regimen, whereas chemotherapy or other aggressive systemic regimens are reserved for those with recalcitrant disease or extracutaneous involvement. There is no evidence that early aggressive systemic therapy is preferable to conservative therapy in the management of limited disease. There are newer combination topical and/or systemic regimens that result in an improved clinical response and possibly a prolonged response duration. For advanced disease, standard therapies are often palliative and successful clinical response is often very short-lived. Therefore, all patients with recalcitrant or extracutaneous disease should be considered for newer investigative therapies.

Abstract

To compare the efficacy of total skin electron beam therapy (TSEBT) with or without adjuvant topical nitrogen mustard (+/- HN2) with topical nitrogen mustard (HN2) alone as initial management of T2 and T3 mycosis fungoides (MF).A retrospective analysis of 148 patients presenting to Stanford from January, 1970 through January, 1995 within 4 months of pathologic diagnosis of MF. Fifty-five patients with T2 and 27 with T3 disease received TSEBT +/- HN2. Fifty-four patients with T2 and 12 with T3 disease received HN2 alone. Boosts with radiotherapy were usually administered to cutaneous tumors of patients with T3 disease.TSEBT +/- HN2 yielded significantly higher complete response (CR) rates than did HN2 alone in patients with T2 and T3 disease (76% vs 39%, p = 0.03 for T2, and 44% vs 8%, p < 0.05 for T3, respectively). In T2 disease, treatment with adjuvant HN2 was associated with a longer freedom from relapse following TSEBT when compared to observation following a CR to TSEBT (p = 0.068). However, no significant differences in survival were observed for different management programs for T2 or T3 disease. In T2 disease, both TSEBT and HN2 were as effective as salvage therapy as when utilized as initial therapy. However, salvage therapy in T3 disease was rarely effective. Limited tumor involvement in T3 disease did not correlate with improved survival compared to more generalized tumorous disease. MF contributed to 27% and 68% of deaths in patients with T2 and T3 disease, respectively.Because of high response rates, management of significantly symptomatic or extensive T2 MF should include TSEBT, and adjuvant HN2 should be administered after a CR to TSEBT. Patients with T2 disease who fail TSEBT or HN2 can be salvaged with the other modality. TSEBT is also an effective treatment for T3 disease. The small subset of patients with limited T3 disease may also be treated with HN2 and local radiotherapy to the tumors. Further investigations are necessary to improve the overall outcome for T3 mycosis fungoides.

Abstract

To document national standards of care for patients receiving radiotherapy as part of curative treatment for Hodgkin's disease.A national survey was conducted of 61 institutions treating 275 patients with Stages I-III Hodgkin's disease and representing six facility type strata. Pretreatment evaluation, radiotherapy treatment parameters, and use of combined modality therapy were assessed.Ann Arbor stage for the 275 patients was as follows: IA, 69 (25%); IB, 7 (3%); IIA, 123 (45%); IIB, 36 (13%); IIIA 23 (8%), IIIB, 14 (5%); unknown, 3 (1%). Pretreatment evaluation included complete blood count for 93%, sedimentation rate in 29%, chest CT in 88%, abdominal CT scan in 87%, and bone marrow biopsy in 81%. Lymphangiograms were obtained in 50% of cases; laparotomy was performed in 46%. The yield of positive findings in the spleen at laparotomy was 6.5 % overall. Facility differences with respect to staging were seen only for the use of gallium scans, which were more commonly used in academic centers (44% vs. 15-23% elsewhere, p<0.001). Radiotherapy was delivered with a linear accelerator in 94% of cases. Treatment simulation was performed for 94% and individualized blocks constructed for 95% overall; however, freestanding facilities had a lower rate of performance of these procedures (78% vs. 98-99% for simulation and 88% vs. 96-99% for customized blocking, p<0.001). The mean supradiaphragmatic dose was 36.74 Gy and the mean subdiaphragmatic dose was 33.81 Gy. Planned combined modality therapy was given in 36% of patients. The use of combined modality therapy by stage was as follows: IA, 11%; IB, 43%; IIA, 30%; IIB, 68%; IIIA, 57%; IIIB, 100%. Chemotherapy was completed prior to radiation in 80% of cases and generally consisted of ABVD (32%), an alternating regimen (25%), or MOPP (22%). Among Stage I/II patients, use of chemotherapy was associated with reduced radiation doses (mean supradiaphragmatic dose 34.53 Gy vs. 38.43 Gy and mean subdiaphragmatic dose 31.27 Gy vs. 34.51 Gy), and reduced volumes of treatment (87% vs. 28% treated to one side of the diaphragm only). Laparotomy was not associated with decreased supra- or subdiaphragmatic radiation doses or decreased volumes of treatment.With the exception of gallium scans, pretreatment evaluation is relatively uniform across facility strata. Increased understanding of prognostic factors in Hodgkin's disease and greater use of planned combined modality therapy for higher risk patients appears to have contributed to a decreased use of and low yield of positive findings for laparotomy. Laparotomy was not associated with reduced radiation volumes or doses. Freestanding radiation facilities had a lower rate than other facility types for the performance of treatment simulation and customized patient blocking.

Abstract

Many patients who present with patch and early plaque stage mycosis fungoides follow an indolent course and survive for many years following diagnosis. A certain subset of patients, however, have rapidly progressive disease leading to accelerated demise. We examined 21 histologic sections from initial biopsies taken from patients with stable disease and 26 from patients with rapidly progressive disease in order to evaluate the role of histology in predicting the disease course. Two or three authors examined each case and scored each of 24 histologic parameters using a previously described four-point scale with no knowledge of the patients' clinical courses. Interobserver agreement was quite high. The only histologic parameter that demonstrated statistical differences between the two groups of patients was degree of acanthosis. The degree of spongiosis, number of eosinophils, amount of hyperconvolution of dermal lymphocytes and density of the dermal infiltrate approached statistical significance but did not attain this level. All of these differences were quite small. No differences were seen for the other 19 parameters. Patients with rapidly progressive disease tended to have more acanthosis, a few more hyperconvoluted dermal lymphocytes, a slightly greater number of eosinophils and perhaps a slightly more dense dermal infiltrate than patients who had stable disease. However, as all of these changes were very slight, it appears unlikely that evaluation of any single biopsy specimen for the histologic parameters we studied is helpful in predicting the prognosis for a specific patient.

Abstract

Mycosis fungoides (MF) can begin as early as the first decade of life. Few studies have reviewed MF in younger patients and none has been large enough to assess prognosis and outcome.We reviewed the clinical characteristics, prognosis, factors related to disease progression, and therapy in patients with MF younger than 35 years of age.Fifty-eight patients were entered into this retrospective cohort analysis. Results: Significantly fewer patients with MF who are younger than 35 years presented with erythroderma (T4) and more with limited patch/plaque (T1) disease than older patients. Duration of skin disease before diagnosis of MF did not vary between the two groups. The long-term survival of younger patients with MF is significantly decreased when compared with a race-, age-, and sex-matched control population (p < 0.001). Disease-specific survivals (DSS) of younger and older patients are similar, but young patients show a slight but significantly better overall DSS (p < 0.02). However, DSS comparison of generalized patch/plaque (T2) and tumor stage (T3) patients with MF showed no significant difference between young and old patients (p=0.47, p=0.59). Patient age was not a significant predictor of survival when controlled for T-stage. Sixteen of 58 young patients with MF have died, 13 because of MF (22%), compared with 138 of 500 older patients (28%) who died as a result of MF. All younger patients with MF who progressed had at least T2 disease at presentation. Fifty of 56 young patients with MF and T1-T3 disease were treated initially with total skin electron beam or topical nitrogen mustard. The response to therapy was similar in younger and older patients with MF.T1 disease is more common and T4 disease is unusual in young patients with MF compared with an older population of patients with MF. Young patients with T1 disease, all of whom were treated with either topical nitrogen mustard or total skin electron beam therapy, or both therapies, showed no disease progression. Overall, young patients with MF showed slightly better DSS, but this was because of differences in stage distribution.

Abstract

The expected event-free survival for patients undergoing high-dose salvage therapy for Hodgkin's disease is 40%-60%. Three-quarters of these patients will relapse in prior sites of disease. Radiation therapy is a very effective local-regional modality in Hodgkin's disease. It is possible that the judicious use of radiation can improve the event-free survival of high-dose salvage programs. Retrospective analysis supports this concept, but the rationale should be incorporated and tested in prospective clinical trials.

Abstract

To evaluate the short and long-term effects of total lymphoid irradiation (TLI) in the treatment of cardiac transplant rejection.Between 1986 and 1995, 48 courses of TLI were delivered to 47 cardiac transplant patients. In 37 patients, TLI was administered for intractable allograft rejection despite conventional therapy while 10 patients received TLI prophylactically. The prescribed radiation dose was 8 Gy in 0.8 Gy fractions twice weekly to mantle and inverted-Y plus spleen fields. Postirradiation follow-up ranged from 6 months to 9.1 years, with a mean of 3.1 years.The actual mean dose was 7.3 Gy delivered over a mean of 39 days. Fifty-six percent of patients required treatment delay or abbreviation because of thrombocytopenia, leukopenia, infection, or unrelated problems. In patients treated for intractable rejection, rejection rates dropped from 0.46 to 0.14 and to 0.06 episodes/patient/month before, during, and after TLI (p < 0.0001). Rejection rates continued to drop throughout follow-up. Prednisone requirements decreased from 0.41 mg/kg before treatment to 0.21 mg/kg afterward (p < 0.0001). The ratio of helper to cytotoxic-suppressor T-cells decreased during TLI from 1.33 to 0.89, and remained low at 0.44, 2-4 months after treatment. Infection rates were not increased and two patients developed malignancy. Rejection rates were high during prophylactic treatment and this protocol was abandoned. Three-year actuarial survival after irradiation was 60% for patients with intractable rejection and 70% for the prophylactic cohort.TLI is an effective treatment for control of intractable cardiac rejection. Episodes of rejection and steroid dosage requirements are decreased for up to 9.1 years. A possible mechanism of action is long term alteration in T-lymphocyte subsets. Patients experience transient bone marrow suppression but no increase in infection or bleeding. Long-term complications of TLI are not appreciably different than conventional immunosuppression.

Abstract

Myeloablative therapy followed by allogeneic bone marrow transplantation (BMT) has proven to be curative therapy in patients with hematologic malignancies. Relapse, however, remains a major cause of treatment failure for patients with advanced disease. During the past 15 years, we have gained considerable experience with the combination of fractionated total-body irradiation (FTBI) and etoposide followed by allogeneic BMT for hematologic malignancies. In an attempt to decrease post-transplant relapse rates, 67 patients under the age of 50 years with high-risk or advanced-stage hematological malignancies received an intensified regimen of FTBI and etoposide plus cyclophosphamide followed by BMT from a genotypically-matched related donor. The regimen consisted of 1320 cGy of FTBI in 11 fractions, 60 mg/kg of etoposide (VP-16), and 60 mg/kg of cyclophosphamide (CY). Fifty-three patients received cyclosporine and prednisone for graft-vs.-host disease (GVHD) prophylaxis and 14 patients received cyclosporine, methotrexate, and prednisone. Diagnosis at BMT included 45 patients with acute leukemia, 7 patients with chronic leukemia, and 15 patients with high-grade non-Hodgkin's lymphoma (NHL). Actuarial disease-free survival (DFS) at 3 years was 42% +/- 12% for the entire group with a median follow-up of 50 months (range 20-74) for 28 patients who remain alive in continued complete remission (CR). Actuarial 3-year-DFS was 38% +/- 14% in 52 patients with acute or chronic leukemia and 60% +/- 25% in 15 patients with NHL with relapse rates of 45% +/- 16% and 21% +/- 11%, respectively. DFS at 3 years was 40% +/- 18% in 32 patients with acute leukemia in 1st relapse or 2nd CR or chronic myelogenous leukemia in accelerated phase, and was 32% +/- 22% in 20 patients with more advanced disease. Regimen related mortality occurred in 9 patients (4, veno-occlusive disease of the liver; 2, multi-organ failure; 1, diffuse alveolar hemorrhage; 1, central nervous system (CNS) hemorrhage; 1, adult respiratory distress syndrome (ARDS). The combination of FTBI, etoposide, and cyclophosphamide followed by allogeneic BMT is an effective and relatively well-tolerated regimen for patients with advanced hematologic malignancies. The role for this regimen should be further defined by prospective clinical trials.

Abstract

We investigated the representation of T cells in patients who had been treated for Hodgkin's disease (HD). We found a marked depletion in both CD4 and CD8 naive T-cell counts that persists up to 30 years after completion of treatment. In contrast, CD4 and CD8 memory T-cell subsets recovered to normal or above normal levels by 5 years posttreatment. Thus, the previously-reported long-term deficit in total CD4 T-cell counts after treatment for HD is due to specific depletion of naive T cells. Similarly, total CD8 T-cell counts return to normal by 5 years only because CD8 memory T cells expand to higher than normal levels. These findings suggest that the treatment (mediastinal irradiation) results in a longterm dysregulation of T-cell subset homeostasis. The profound depletion of naive T cells may explain the altered T-cell function in treated patients, including the poor response to immunization after treatment for HD. Further, in some individuals, we identified expansions of unusual subsets expressing low levels of CD8. Eight-color fluorescence-activated cell sorting analyses showed that these cells largely express CD8alphaalpha homodimers and CD57, consistent with the phenotype of potentially extrathymically derived T cells. In addition, these cells, both CD4+ and CD4-, are probably cytotoxic lymphocytes, as they express high levels of intracellular perforin. In adults treated for HD, an increased activity of extrathymic T-cell differentiation may partially compensate for the loss of thymic-derived T cells.

Abstract

Lymphomas of the paranasal sinuses may have poorer prognoses compared with other extranodal lymphomas of the head and neck, and are not well defined as a particular clinicopathologic entity. The outcome of combined-modality therapy and central nervous system (CNS) prophylaxis has not been fully determined.We retrospectively reviewed our experience with 16 consecutive, carefully defined patients, all treated with both chemotherapy and radiotherapy.There were 11 men and five women, mean age 52. All presented with local symptoms; 13 had stage I or II disease. Thirteen had diffuse large cell lymphoma, two diffuse mixed, and one small noncleaved. Phenotyping revealed 10 B-cell, four T-cell, and two T or natural killer (NK). Most received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy; the order of chemotherapy and radiotherapy varied. Twelve received CNS prophylaxis. Of 12 complete responses, six relapsed, all at distant sites, and two died during initial therapy. Five-year survival was 29%, and median survival 18 months. Four of 10 B-lineage patients were relapse-free at 4 years; all six T- or T/NK-lineage patients relapsed or were dead within 6 months. Tumors of T or NK lineage often expressed CD56 and showed evidence of Epstein-Barr viral infection; otherwise, pathological features were not predictive of lineage or outcome. Neither age nor lactate dehydrogenase predicted prognosis. No complete responder recurred in the CNS as site of first relapse.Despite localized stage at presentation, sinus lymphoma is an aggressive disease, characterized by distant relapse and early mortality. Combined-modality therapy with CNS prophylaxis improves outcome compared with radiotherapy alone; however, prognosis remains poor. Patients with T-lineage disease appear to have a particularly bad outcome. Autologous bone marrow transplantation should be evaluated as first-line therapy for those at high risk of relapse.

Abstract

We have demonstrated that a relatively mild chemotherapy regimen, vinblastine, methotrexate, and bleomycin (VBM), and involved-field radiotherapy (IFRT) could substitute for extended-field radiotherapy in patients with favorable Hodgkin's disease (HD) who have been laparotomy-staged. The purpose of this study is to determine if VBM and regional radiotherapy can substitute for extended-field radiotherapy in favorable clinical stage (CS) I and II HD.Seventy-eight patients with favorable CS I to II HD were randomly assigned to subtotal lymphoid irradiation (STLI) or VBM chemotherapy and regional radiotherapy. Randomization was stratified on the basis of age, sex, number of Ann Arbor sites, histology, and institution. Patients were evaluated for freedom from progressive HD, survival, and toxicity. Results were compared with the predecessor trial in pathologically staged patients.With a median follow-up period of 4 years, the rate of freedom from progressive HD was 92% (95% confidence interval [CI], 88% to 96%) for patients treated with STLI and 87% (95% CI, 81% to 93%) for patients treated with VBM and regional radiotherapy. Six of seven patients who relapsed are alive and in remission following successful second-line therapy.Given the caveat of a small number of patients, the results of extended-field radiotherapy and VBM and regional radiotherapy are comparable with a median follow-up period of 4 years. VBM serves as a paradigm to reduce late effects in favorable early-stage HD. We do not advocate its routine use in clinical practice, but instead encourage participation in clinical trials with the objective of maintaining efficacy while reducing toxicity in CS I and II HD.

Abstract

To examine the costs and benefits of routine follow-up evaluation in patients treated with radiation therapy for early-stage Hodgkin's disease.We retrospectively examined patterns of follow-up evaluation and methods of relapse detection among 709 patients with stage I and II Hodgkin's disease treated with primary radiotherapy between 1969 and 1994. We determined the probability of relapse detection for seven routine follow-up procedures, compared their relative costs, and determined the impact of each procedure on the likelihood of survival following salvage therapy.Relapse has occurred in 157 patients (22%) at a median 1.9 years (range, 0 to 13 years) posttreatment. Relapse was suspected primarily by history (Hx) in 55% of patients, physical examination (PE) in 14%, chest x-ray (CXR) in 23%, and abdominal x-ray (KUB) in 7%. Only one relapse (1%) was identified by a routine laboratory study. The rate of relapse detection was highest for a combination of Hx and PE (78 of 10,000 examinations) followed by CXR (26 of 10,000 examinations). The projected charges (1995 dollars) per relapse detected by routine follow-up Hx and PE were $11,000 compared with $68,000 for CXR and $142,000 for KUB. The 10-year actuarial survival rate following salvage therapy was 65% overall, 65% for patients in whom relapse was detected by Hx or PE, and 69% for patients in whom relapse was detected by radiographs (P = not significant).The majority of relapses occurred within 5 years of treatment and were identified by Hx and PE. CXR was useful during the first 3 years of follow-up evaluation. KUB, CBC, and laboratory studies accounted for nearly half of all follow-up charges and rarely led to the detection of relapse. Their routine use as a method of relapse detection is questionable. In general, the method of relapse detection did not have a significant impact on the likelihood of successful salvage therapy.

Abstract

One hundred nineteen patients with relapsed or refractory Hodgkin's disease (HD) received high-dose therapy followed by autologous hematopoietic progenitor cell transplantation. Three preparatory regimens, selected on the basis of prior therapy and pulmonary status, were employed. Twenty-six patients without a history of prior chest or pelvic irradiation were treated with fractionated total body irradiation, etoposide (VP) 60 mg/kg and cyclophosphamide (Cy) 100 mg/kg. Seventy-four patients received BCNU 15 mg/kg with identical doses of VP and Cy. A group of 19 patients with a limited diffusing capacity or history of pneumonitis received a novel high-dose regimen consisting of CCNU 15 mg/kg, VP 60 mg/kg and Cy 100 mg/kg. Twenty-nine patients (24%) had failed induction therapy and 35 (29%) had progressive HD within 1 year of initial chemotherapy. At 4 years actuarial survival was 52%, event-free survival was 48% and freedom from progression (FFP) was 62%. No significant differences were seen in survival data with the three preparatory regimens. Six patients died within 100 days of transplantation and 5 died at a later date of transplant-related complications. Secondary malignancies have developed in 6 patients, including myelodysplasia/leukemia in four patients and solid tumors in two patients. Regression analysis identified systemic symptoms at relapse, disseminated pulmonary or bone marrow disease at relapse and more than minimal disease at the time of transplantation as significant prognostic factors for overall and event-free survival and FFP. Patients with none of these factors enjoyed an 85% FFP at 4 years compared with 41% for patients with one or more unfavorable prognostic factors (P = .0001). Our results confirm the efficacy of high-dose therapy and autografting in recurrent or refractory HD. Although longer follow-up is necessary to address ultimate cure rates and toxicity, our data indicate that a desire to reduce late effects should drive future research efforts in favorable patients whereas new initiatives are needed for those with less favorable prognoses.

Abstract

Sixty patients with Hodgkin's disease, refractory to or at first recurrence after chemotherapy, received cytoreductive therapy followed by high-dose etoposide, cyclophosphamide and either total body irradiation or carmustine and autografting (median follow-up, 3.6 years; range, 1.1 to 7.5 years). A matched conventional salvage group of 103 patients was selected from patients treated at Stanford University Medical Center between January 1976 and January 1989 (median follow-up, 10.3 years; range, 3.0 to 15.7 years). Overall survival (OS), event-free survival (EFS), and freedom from progression (FFP) at 4 years follow-up favored patients who received high-dose therapy compared with conventional salvage treatment (OS: 54% v 47%, P = .25; EFS: 53% v 27%, P < .01; FFP: 62% v 32%, P < .01). In Cox regression analysis, response to cytoreductive or salvage therapy and B symptoms at relapse were the most important predictors of OS. The use of high-dose therapy at relapse, a longer duration of remission, and favorable response to cytoreductive or salvage therapy were most predictive of superior FFP and EFS. These data from a single institution comparing conventional and high-dose therapy in matched patients demonstrate an advantage for high-dose therapy and autografting in the sustained control of Hodgkin's disease. As with primary therapy, it is difficult to demonstrate a statistically significant survival advantage, despite an apparently superior cure rate. However, patients failing induction therapy or relapsing within 1 year benefited significantly from high-dose therapy by all outcome measures (OS, EFS, FFP). As the transplant-related mortality rates decline in Hodgkin's disease, it is predicted that cure rates and late effects will become ultimate determinants of the success of high-dose therapy and autografting.

Abstract

The Patterns of Care Study (PCS) surveys for Hodgkin's disease have documented important correlations between treatment processes and patient outcome. Nationwide improvements in radiotherapy for Hodgkin's disease since 1973, such as routine use of extended fields (subtotal lymphoid irradiation) in patients with early stage disease, individualized blocking, and treatment using linear accelerators, have resulted in greater freedom from relapse and overall survival for patients with stage I/II disease treated with radiotherapy alone. In addition, the introduction of computed tomography along with increased use of chemotherapy in high-risk patients has reduced the use of routine laparotomy and has improved outcome for patients with stage III disease. Overall survival for Hodgkin's disease in the national practice is excellent, reflecting the dissemination of complex treatment programs and radiation therapy technology to the oncologic community at large. Future studies of the national practice will be important in assessing the impact of managed care on workup and other facility practices, as well as evaluating the transfer of new approaches aimed at reducing treatment toxicities.

Abstract

The long-term survival of patients treated for Hodgkin's disease permits careful evaluation of long-term complications and excess mortality.Between 1960 and 1995, 2498 patients who were treated for Hodgkin's disease at Stanford University were evaluated. Survival, freedom from relapse, and important complications of therapy (cardiac disease and secondary cancers) were analyzed, and risk of mortality from all causes was calculated utilizing absolute excess risk calculations.The risk of death from Hodgkin's disease is 17% at 15 years of follow-up and increases only slightly thereafter. The risk of death from other causes is also 17% at 15 years, but increases sharply thereafter. The major causes of mortality (other than Hodgkin's disease) are secondary cancers and cardiac disease. Second cancers with significant increase in risk include leukemia (acute nonlymphocytic), non-Hodgkin's lymphoma, lung/pleural cancer, breast cancer, melanoma, soft tissue and bone sarcomas, stomach cancer, salivary gland tumors, thyroid cancer, and pancreatic cancer. The absolute excess risk of death from causes other than Hodgkin's disease increases during each five-year follow-up interval for at least 25 years. However, the absolute excess risk of death during similar follow-up periods is less for patients treated in more recent years (1980-1995) than in the prior treatment era (1962-1980).Mortality for causes other than Hodgkin's disease is important in the long-term follow-up of patients. Causes of death are often treatment related. Changes in treatment programs can reduce the long-term excess risk of death from complications of therapy.

Abstract

This study aimed to quantify the risk of gastrointestinal cancer following Hodgkin's disease treatment according to age at treatment, type of treatment, and anatomic sites.Cases were identified from the records of 2,441 patients treated for Hodgkin's disease between 1961 and 1994. Follow-up averaged 10.9 years, representing 26,590 person-years of observation. Relative risks (RR) for gastrointestinal cancer incidence and mortality were computed by comparison with expected annualized rates for a general population matched for age, sex, and race.Gastrointestinal cancers developed in 25 patients. The incidence RR was 2.5 [95% confidence interval (CI), 1.5-3.5] and mortality RR was 3.8 (CI, 2.4-4.7). Sites associated with significantly increased risks included the stomach [RR 7.3 (CI, 3.4-13.8)], small intestine [RR 11.6 (CI, 1.9-38.3)], and pancreas [RR 3.5 (CI, 1.1-8.5)]. Risk was significantly elevated after combined modality therapy, RR 3.9 (CI, 2.2-5.6). The risk after radiotherapy alone was 2.0 (CI, 1.0-3.4), not a statistically significant elevation. The RR for gastrointestinal cancer was greatest after treatment at young age and decreased with advancing age. It was significantly elevated within 10 years after treatment [RR 2.0 (CI, 1.1-3.5)] and increased further after 20 years [RR 6.1 (CI, 2.5-12.7)]. Risk assessed by attained age paralleled risk according to age at treatment. Fifteen cases of gastrointestinal cancers arose within the irradiation fields.Patients treated for Hodgkin's disease are at modestly increased risk for secondary gastrointestinal cancer, especially after combined modality therapy and treatment at a young age. Risk was highest more than 20 years after treatment, but was significantly elevated within 10 years. Gastrointestinal sites with increased risk included the stomach, pancreas, and small intestine.

Abstract

To study the long-term results of treatment of patients with stage IA mycosis fungoides and analyze the factors related to disease progression and the effect of initial therapy on survival and freedom from relapse.A single-center, 32(1/2)-year, retrospective cohort analysis.Private referral medical center.One hundred twenty-two patients with clinical stage IA (T1, N0, M0) mycosis fungoides.Long-term actuarial survival and freedom-from-relapse results as calculated by the technique of Kaplan-Meier.The long-term (30-year) survival of patients with stage IA mycosis fungoides is similar to the expected survival of a race-, age-, and sex-matched control population. The median survival of this group has not been reached at 32(1/2)-years. Eleven patients (9%) who progressed to more advanced disease had a lower complete response rate to initial therapy than did other patients (36% vs 82%) and an older mean age than did other patients with T1 disease (61 vs 48 years, P < .05). Only 3 (2%) of 122 patients died of disease. Among stage IA patients who achieved a complete response, 25% are relapse free at 10 years. Patients who received total skin electron beam therapy (n = 34) had a more favorable freedom-from-relapse outcome than those treated with topical mechlorethamine hydrochloride (nitrogen mustard) (n = 73, P < .05). No significant difference was seen in the long-term survival between the 2 treatment groups.Patients with clinical stage IA mycosis fungoides treated at Stanford University do not have an altered life expectancy. Fewer than 10% progressed to more advanced stages and few died of disease. Although the response rate to total skin electron beam therapy was superior to that of topical mechlorethamine, the longterm survival results were similar. Topical mechlorethamine is a cost-effective and convenient therapy for patients with limited patch and plaque mycosis fungoides.

Abstract

The use of high-dose chemotherapy with or without total-body irradiation (TBI) followed by autologous hematopoietic cell transplantation is associated with improved survival for relapsed or refractory non-Hodgkin's lymphoma (NHL). Previous reports comparing preparatory regimens with or without TBI followed by autologous bone marrow transplantation (ABMT) or peripheral blood progenitor cell transplantation (PBPCT) for these patients did not demonstrate any survival difference between the different modalities. No randomized studies comparing survival for patients with NHL transplanted with radiochemotherapy vs. chemotherapy alone have been reported. We treated 221 patients with high-risk, relapsed or refractory NHL with either chemotherapy alone or radiochemotherapy followed by ABMT or PBPCT. The patients were assigned preparatory regimens in a non-randomized manner and this analysis was performed to evaluate differences in outcome with the two preparatory regimens. Actuarial five-year event-free survival (EFS) was similar in patients receiving fractionated total-body irradiation (FTBI) plus etoposide (VP-16) and cyclophosphamide (Cy) compared with chemotherapy alone consisting of carmustine (BCNU) plus identical doses of VP-16 and Cy (52% vs. 46%, p = 0.08). Overall survival (OS) favored radiochemotherapy (61%) compared with chemotherapy alone (53%, p = 0.02). The relapse rate was the same in both groups (41%), whereas the transplantation-related mortality (TRM) was similar in patients receiving chemotherapy alone and those receiving radiochemotherapy (13% vs. 7% respectively, p = 0.30). Proportional hazards analysis of significant variables including preparatory regimen found only the number of prior relapses to be predictive of EFS. Fewer number of prior relapses, radiochemotherapy and PBPCT were significant predictors of favorable OS. In additional analyses, the improved OS of the radiochemotherapy regimen was confirmed only for patients receiving ABMT but was not a significant predictor of outcome in patients transplanted with PBPCT. From these retrospective data we conclude: 1) PBPCT resulted in survival superior to that of ABMT; 2) the risk of relapse is similar with either preparatory regimen; 3) patients with fewer prior relapses enjoyed superior overall and event-free survival as well as fewer relapses; and 4) there were no significant differences in the two preparatory regimens when combined with PBPCT in relapsed or refractory NHL.

Abstract

To evaluate retrospectively the results of radiotherapy for 177 patients with stage I (n = 73 [41%]) and II (n = 104 [59%]) follicular small cleaved-cell and follicular mixed small cleaved-cell and large-cell non-Hodgkin's lymphoma (NHL) treated in the Department of Radiation Oncology, Stanford University between 1961 and 1994.Histology was follicular small cleaved-cell in 101 (57%) cases and follicular mixed small cleaved-cell and large-cell in 76 (43%). Forty-five patients (25%) had staging laparotomy; 34 (19%) had extranodal involvement. All patients had received radiotherapy, either to one side of the diaphragm (involved or extended field) or to both sides (total lymphoid irradiation [TLI] or subtotal lymphoid irradiation [STLI]. Radiotherapy doses ranged from 35 to 50 Gy.The median follow-up duration was 7.7 years. The longest follow-up duration was 31 years. Actuarial survival rates at 5, 10, 15, and 20 years were 82%, 64%, 44%, and 35%, respectively. The median survival time was 13.8 years. At 5, 10, 15, and 20 years, 55%, 44%, 40%, and 37% of patients, respectively, were relapse-free. Only five of 47 patients who reached 10 years without relapse subsequently developed recurrence. Survival and freedom from relapse (FFR) were significantly worse for older patients. Relapse rates were lower following treatment on both sides of the diaphragm or staging laparotomy. Univariate analysis showed that youth and staging laparotomy were associated with significantly better survival and that FFR was better following treatment on both sides of the diaphragm or laparotomy.Radiotherapy remains the treatment of choice for early-stage low-grade follicular lymphomas. Patients who have remained free of disease for 10 years are unlikely to relapse.

Abstract

Chimeric anti-CD4 monoclonal antibody was administered intravenously as a single dose to eight patients with mycosis fungoides. The dose was escalated throughout the study between patients groups, and individual patients received 50, 100, or 200 mg per dose. Seven of eight patients responded to treatment with an average freedom from progression of 25 weeks (range, 6 to 52 weeks). The treatment was well tolerated, and there was no clinical evidence of immunosuppression. Following treatment, there was significant suppression of peripheral blood CD4 counts in all patients for 1 to 22+ weeks. Only one patient made a very low titer human antichimeric antibody response. All but two patients made primary antibody and T-cell proliferative responses to a foreign antigen administered 24 hours after antibody infusion. However, there was generally marked, but temporary suppression of T-cell proliferative responses in vitro to phytohemagglutinin (PHA), tetanus toxoid, and normal donor lymphocytes. We conclude that at the dose levels studied, this antibody (1) had clinical efficacy against mycosis fungoides; (2) was well tolerated; (3) had a low level of immunogenicity; (4) decreased T-cell proliferative responses in vitro, and (5) did not induce tolerance to a foreign antigen.

Abstract

The success of radiation therapy (XRT) in the management of early-stage Hodgkin's disease (HD) has led to its use in a variety of programs for the management of advanced disease. This article includes discussion of these roles of radiation in advanced disease: 1) use of XRT as an adjuvant after chemotherapy; 2) use of XRT to convert patients who are 'partial responders' (PRs) after chemotherapy to 'complete responders' (CRs); 3) use of XRT as an integrated component of combined modality therapy; 4) use of XRT as a 'salvage' treatment after failure of primary chemotherapy; and 5) incorporation of XRT into programs of high-dose therapy with autologous stem cell (or marrow) rescue. 1) Randomized trials of adjuvant XRT after completion of chemotherapy in advanced disease have been conducted by the Southwest Oncology Group (SWOG), German HD Study Group, and the European Organization for the Research and Treatment of Cancer/Group Pierre Marie Curie (EORTC/ GPMC). The SWOG study shows improvements in disease-free survival, but not overall survival with the addition of XRT. The German Study Group trial was negative, but the number of patients reported in the abstract of the trial was too small to be conclusive. The EORTC/GPMC study has not been reported. 2) Both the SWOG and EORTC/GPMC trials treated "PRs' with XRT. Results in both show conversion to CR in > 80% of patients. Conversion to CR was most likely for patients with just minimal residual disease after chemotherapy. 3) Planned XRT in advanced disease (especially bulky sites) may permit reduction in chemotherapy doses (e.g., the Stanford V chemotherapy program) and maintain excellent outcome (freedom-from-progression > 80%). Reduction in total doses of chemotherapy as well as dose and extent of radiation should limit potential long-term toxicity. 4) Very selected patients with asymptomatic limited nodal relapse may be "salvaged' with XRT, but published reports include only a small number of patients and this should not be considered a standard approach. 5) XRT may be used as total body, total lymphoid, or local field in high-dose therapy programs. Since HD at relapse is still often a local-regional problem, local field irradiation is probably the most rational approach to use in this setting. Recent Stanford data show an improvement in outcome with the inclusion of local field treatment in these patients.

Abstract

From May 1989 to August 1995, 94 previously untreated patients with Hodgkin's disease stage II with bulky mediastinal involvement (n = 28) or stage III or IV (n = 66) received an abbreviated chemotherapy regimen, Stanford V, +/-radiotherapy (RT). Chemotherapy was given weekly for 12 weeks followed by consolidative RT to sites of initial bulky disease. With a median follow-up of 3 years, the actuarial 6-year survival is 93% and the freedom from progression is 89%. There have been no relapses or deaths among the 28 patients with stage II bulky mediastinal disease. Eight relapses and three deaths have occurred in the group of 66 patients with stage III-IV disease. The abbreviated chemotherapy regimen, Stanford V, in combination with RT is well tolerated and highly effective therapy for bulky, limited stage and advanced stage HD. Lower cumulative exposure to alkylating agents, doxorubicin, bleomycin and limited use of radiation is expected to improved the prospects for fertility and decrease the risks for second neoplasms and late cardiopulmonary toxicity.

Abstract

The majority of newly diagnosed patients are expected to survive Hodgkin's disease because of effective therapies established during past 30 years. Long-term observations from large populations of treated patients have disclosed a variety of late effects of the disease and its therapy have contributed morbidity and excess mortality to Hodgkin's disease survivors. Secondary cancers have continued to accrue, and the risk relative to the general population has increased to 6.4 (95% confidence intervals: 5.5 to 7.3) in updated experience at Stanford University. Risks are significantly elevated for leukemia (primarily after chemotherapy regimens containing alkylating agents); non-Hodgkin's lymphoma; and tumors of the lung, breast, soft tissues, bone, stomach, pancreas, salivary gland, thyroid, and cutaneous melanoma. Early cardiovascular disease has also been observed and numerically exceeds second cancers as a cause of death in patients with early stage Hodgkin's disease (49 v 47 cases). Pulmonary dysfunction, thyroid dysfunction, infertility, psychosocial changes, gastrointestinal problems, soft-tissue changes, alterations in immunity, and risks for infection have also affected some treated patients. As these problems have been recognized, treatment approaches have been modified over the last 10 to 15 years, and early data suggest a decrease in some treatment sequellae.

Abstract

There are no large studies evaluating patients with erythrodermic mycosis fungoides and Sézary syndrome to determine the important prognostic factors that may influence survival. This is important since new treatment modalities have been proposed as superior to existing primary therapies. We performed a retrospective cohort study of 106 patients with erythrodermic mycosis fungoides and Sézary syndrome, followed up in the Stanford (Calif) Mycosis Fungoides Clinic, to define the important prognostic factors in this group.Patients younger than 65 years have a more favorable survival profile than those 65 years or older (P < .005). Longer duration of symptoms before diagnosis ( > or = 10 years) tends to be associated with more favorable prognosis (p = .055). Lymph node stage is significantly correlated with survival; patients with overall stage III disease have more favorable prognosis than those with stage IV disease (P < .001). Patients with circulating Sézary cells in their blood have a significantly worse prognosis than those without (P < .005). Patient sex or race had no significant effect on overall survival outcome. Three distinct prognostic groups were identified, "favorable," "intermediate," and "unfavorable," according to the number of unfavorable prognostic factors (P < .005). The median survival in each group is 10.2, 3.7, and 1.5 years, respectively.In patients with erythrodermic mycosis fungoides and Sézary syndrome, the important prognostic factors are patient age at presentation, the overall stage, and peripheral blood involvement. Survival varies widely, depending on these variables. These prognostic factors should be evaluated when analyzing survival and/or treatment efficacy data of these patients.

Abstract

A retrospective analysis was undertaken to determine the indications for, the efficacy of, and the long-term complications of two courses of total skin electron beam therapy for mycosis fungoides.A retrospective analysis of 15 patients with the pathologic diagnosis of mycosis fungoides treated in the Department of Radiation Oncology at Stanford University Medical Center between 1968 and 1990 was performed. All patients received two courses of high-dose electron beam therapy to the skin. The mean dose for the total skin treatment for the first course was 32.6 Gy and 23.4 Gy for the second course of treatment.Following the first course of total skin electron beam therapy, 11 of 15 had a complete response, with a mean duration of 11.6 months. All patients received adjuvant therapies between the first and second courses of high-dose total skin electron beam therapy. The mean interval between the first and the second courses of therapy was 41.3 months. Patients were restaged prior to commencement of their second course of high-dose total skin electron beam therapy, resulting in upstaging in six. The second course of therapy resulted in six complete responses and nine partial responses. Twelve of these patients have since died, 1 is lost to follow-up, and 2 are living with disease. The long-term side effects in the two living patients include pigmentation changes, alopecia, and diffuse xerosis.Delivery of two courses of total skin electron beam therapy is technically feasible, tolerable, and efficacious. The dose to the total skin was reduced for the second course of therapy in all cases. The criteria used to screen patients included initial good response to total skin electron treatment, long disease-free interval, exhaustion of other therapeutic modalities, and generalized skin involvement at relapse. Long-term toxicities were mild in severity and generally consisted of generalized xerosis, scattered telangiectasias, pigmentation changes, and partial alopecia.

Abstract

To evaluate the time of onset, method of identification, management, and outcome of pelvic relapse following subtotal lymphoid irradiation (STLI) alone (mantle and paraaortic/spleen or splenic pedicle fields, excluding the pelvis) in supradiaphragmatic Stage I-II Hodgkin's disease.A retrospective analysis was performed of the initial, relapse, and regular follow-up evaluations of patients with pelvic relapse following STLI alone from 1968 to the present for supradiaphragmatic Stage I-II Hodgkin's disease after pathologic staging (PS-laparotomy staging) and clinical staging (CS-no laparotomy staging).Following staging, which included bipedal lymphangiography, 482 patients (408 PS and 74 CS), were treated with STLI alone for supradiaphragmatic Stage I-II Hodgkin's disease. The actuarial freedom from relapse at 20 years was 75% in PS patients and 81% in CS patients. The actuarial pelvic failure at 20 years was 7% for PS patients and 3% for CS patients. Of the 29 patients with pelvic relapse, 97% (28 of 29) occurred within 5 years of treatment, including 1 patient who progressed during initial treatment. Pelvic relapse was most commonly initially identified by abnormalities involving patient symptoms (62%), physical examination (55%), erythrocyte sedimentation rate (48%), and bipedal lymphangiogram and/or abdominal radiograph (38%). Relapse was limited to previously unirradiated sites in 17 patients (58%). In addition to pelvic lymph node disease, 3 patients (10%) had involvement of bone, and 4 patients (14%) had bone marrow involvement. Following relapse, all patients were treated with chemotherapy (MOP[P], MOP[P]/ABV[D], ABVD, or PAVe) and 19 of 29 patients received involved field consolidative irradiation. Twenty-one of 29 (72%) remained relapse free at the time of last follow-up evaluation, including 15 of 19 (79%) treated with combined therapy. Eight patients experienced a second relapse despite salvage therapy, and all eight expired with recurrent Hodgkin's disease. Two patients died of complications related to prior treatment. Therefore, the actuarial risk of death at 20 years associated with pelvic failure in the entire cohort of 482 patients was 2%.Pelvic relapse occurred in 7% of patients following STLI alone and was effectively diagnosed by regular follow-up, which included a combination of patient history, physical examination, and radiographic laboratory evaluation. Seventy-two percent of patients remained relapse free following salvage treatment, which included chemotherapy, resulting in an overall survival rate associated with pelvic control of 98%. This approach, therefore, spared the majority of patients the long-term risks associated with pelvic irradiation and/or chemotherapy, such as infertility, but maintained an excellent prognosis.

Abstract

Although survival rates have improved for patients with bulky and advanced-stage Hodgkin's disease (HD), current treatments entail substantial acute morbidity and risks for late effects such as infertility, second malignancies, and cardiopulmonary toxicities. A novel, brief chemotherapy regimen (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone [Stanford V]) was designed to shorten the duration of treatment, significantly reduce cumulative doses of alkylating agents, doxorubicin, and bleomycin, and maintain dose-intensity (DI). This brief chemotherapy was combined with radiation therapy (RT) to bulky disease sites.Since May 1989, 65 previously untreated patients were treated for stage II HD with bulky mediastinal involvement (n = 21) or for stage III or IV HD (n = 44). Patients received weekly chemotherapy for 12 weeks. Consolidative RT was given to the first 25 patients to sites of initial bulky disease or radiographic abnormalities that persisted after chemotherapy; in the remaining 40 patients, RT was limited to bulky disease (adenopathy > or = 5 cm and/or macroscopic splenic nodules defined by computed tomography [CT]).With a median follow-up period of 2 years, actuarial 3-year survival rate is 96% and failure-free survival (FFS) rate is 87%. The 3-year FFS rate is 100% for stage II patients with bulky mediastinal disease and 82% for patients with stage III to IV disease. There were no treatment-related deaths. In a preliminary analysis on a subset of patients, female and male fertility appears to be preserved.These preliminary results indicate that the Stanford V chemotherapy regimen with or without RT is well-tolerated and effective therapy for bulky, limited-stage, and advanced-stage HD. Less cumulative exposure to alkylating agents, doxorubicin, and bleomycin and limited use of radiation is expected to decrease risks for second neoplasms and late cardiopulmonary toxicity. Based on these results, the Stanford V chemotherapy with or without RT regimen deserves further study in the context of a randomized clinical trial.

Abstract

Nonneoplastic mononuclear cells commonly infiltrate lesions of mycosis fungoides.We sought to determine the immunophenotypic characteristics of these cells and to determine whether the presence of CD8+ tumor-infiltrating lymphocytes has an impact on prognosis.Skin biopsy specimens from 78 patients were stained with immunopleroxidase techniques to determine their phenotypic characteristics. The proportion of CD8+ tumor-infiltrating lymphocytes was quantified and compared with stage of disease and survival rate.Patients with more limited T-stage disease tended to have a higher proportion of CD8+ cells in their skin biopsy specimens, compared with patients with more advanced T-stage disease. Within each T-stage patients with a larger proportion of CD8+ cells had a better survival rate than those with fewer CD8+ cells (p < 0.05 for T1 and T3). A multivariate analysis confirmed the importance of T stage (p = 0.0006), overall stage (p = 0.0112), and CD8 positivity (p = 0.0335) in this cohort of patients.CD8+ tumor-infiltrating lymphocytes in mycosis fungoides correlate with improved survival rate and may exert an antitumor effect rather than being mere bystander cells.

Abstract

High-dose etoposide was incorporated into a regimen of fractionated total-body irradiation (FTBI) and high-dose cyclophosphamide before autologous transplant with the goal to enhance the antitumor effect of the myeloablative regimen in poor-risk lymphoid malignancies.Ninety-six patients, 24 with recurrent or refractory Hodgkin's disease and 72 with poor-risk non-Hodgkin's lymphoma (NHL), were treated on this study. Cytoreduction with conventional therapy was attempted before administration of the preparatory regimen. The preparatory regimen consisted of 12 Gy total-body irradiation administered in 10 1.2-Gy fractions on day -8 through day -5, etoposide 60 mg/kg on day -4, and cyclophosphamide 100 mg/kg on day -2. Patients with NHL received bone marrow purged with a panel of monoclonal antibodies and complement on day 0, while patients with Hodgkin's disease received peripheral-blood stem cells alone or with unmanipulated bone marrow.The major morbidities of transplant were mucositis and skin toxicity. Eight patients (8.6%) died of regimen-related toxicities within 100 days of transplant. Engraftment was related to the rescue product; the median time to a neutrophil count more than 500/microL was 10 days for patients with Hodgkin's disease and 16 days for NHL patients. With a maximum follow-up duration of longer than 5 years, the 3-year actuarial survival rate is 57%. At 3 years, the actuarial freedom from progression (FFP) rate is 55% and the event-free survival rate is 47% for patients with Hodgkin's disease, while the respective figures for NHL patients are 60% and 53%. Among 32 patients with intermediate- and high-grade lymphoma transplanted subsequent to first relapse, 70% are free of lymphoma and 60% are event-free at > or = 3 years.The preparatory regimen consisting of FTBI, etoposide, and cyclophosphamide demonstrates relative efficacy in patients with Hodgkin's disease and NHL selected for high-dose therapy. Longer follow-up duration is needed to determine the rate of cure and to assess late complications. Major remaining challenges for high-dose therapy are a more inclusive strategy for all poor-risk patients and the need to reduce posttransplant relapses.

Abstract

The treatment of early-stage gastric lymphoma is controversial. This retrospective analysis reports on the outcome of 24 patients treated in our institution during the past 25 years. Fourteen patients had stage IEA, one patient had IEB, six patients IIEA1, and three patients had stage IIEA2 non-Hodgkin's lymphoma (NHL). Diffuse large cell intermediate-grade NHL was diagnosed in 17 patients, diffuse small cleaved cell in three patients, and diffuse mixed large and small cell lymphosarcoma, low-grade B-cell lymphoma, and unclassified lymphoma in one patient each. Fourteen patients underwent surgery, 21 had radiation therapy (XRT), and 10 patients received chemotherapy. Surgery + XRT were given to 7 patients, surgery + XRT + chemo and XRT alone were delivered to five patients each, and XRT + chemotherapy were employed in four patients. Surgery alone was the initial treatment in two patients and chemotherapy alone was given to one patient. Following treatment 22/24 achieved a complete response. During a mean follow-up period of 77.6 months (range 1-285), five patients relapsed. At 10 years, the actuarial survival of the 15 patients with stage I disease was 57.4% and for stage II it was 51.9% (Gehan P-value 0.33). Freedom from relapse (FFR) was 60.7% and 58.3%, respectively (P-value 0.56). No significant statistical differences in terms of survival and FFR were noted in patients treated with surgery, chemotherapy, or XRT. The outcome of patients treated with triple-modality therapy was similar to those treated with double-modality therapy and to patients treated with XRT alone. Gender, age, presenting symptoms, depth of tumor through the gastric wall, and stage were not statistically significant for prediction of either survival or FFR. Both surgery + XRT and chemotherapy + XRT are effective in the treatment of early-stage gastric disease. XRT alone is equally effective as two or three modality treatments in the subset of patients with early-stage gastric lymphoma. However, the low number of patients treated with various approaches over a long period precludes a firm conclusion. Until prospective randomized studies are initiated, management programs should be individually tailored.

Abstract

Because each of very different treatments for Hodgkin's disease (HD) may result in a high rate of cure, attention is currently focused on toxicity. This prospective study was designed to assess the effects of mediastinal irradiation and bleomycin chemotherapy on pulmonary function.Patients were treated from 1980 to 1990 on randomized controlled trials at Stanford University. Pulmonary function was tested before treatment (baseline), early after treatment (< 15 months), and more than 36 months posttherapy. Treatment options in the 145 patients were grouped as I (mediastinal radiotherapy), II (mediastinal radiotherapy plus bleomycin), and III (bleomycin) for analyses of variance (ANOVAs). A variety of regression models were used to predict early and late effects on pulmonary function.A decrease in forced vital capacity (FVC) and diffusing capacity (DLCO) in the first 15 months after treatment followed by recovery after 36 months was observed for most patients. Patients who received mediastinal radiotherapy (RT) had a more pronounced reduction in pulmonary function and less complete recovery. Overall, 3 or more years after treatment, 32% of group I patients, 37% of group II patients, and 19% of group III patients had FVC values less than 80% of predicted, while only 7% of patients had a DLCO less than 80% of predicted. Linear regression identified baseline measurement as the only significant predictor of change in percent predicted FVC or DLCO; patients with higher baseline values had greater decrements after therapy. Mantle RT was the only significant treatment variable, predictive of FVC and DLCO within 15 months and FVC at 36 or more months. No patient experienced pulmonary toxicity severe enough to require hospitalization.This prospective analysis of pulmonary function after treatment for HD showed that mediastinal RT was the only treatment variable that achieved statistical significance. Although there were no significant interactions between mediastinal RT and bleomycin or Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) chemotherapy, the patient numbers were small after correction for mediastinal mass size and drug regimen such that an effect could have been missed. The mild reduction in pulmonary function should be factored into the overall assessment of morbidity risk for each of the potentially curative treatments included in this study. As with all reports of late effects, these data should be interpreted with respect to the population tested, details of the treatment administered, methods of measurement, and length of follow-up.

Abstract

To evaluate the effect of filgrastim (recombinant human G-CSF) on radiation-induced neutropenia in a well defined, homogenous patient population.Seven patients who were to receive large field subdiaphragmatic irradiation after thoracic "mantle" fields for treatment of Hodgkin's disease entered this study. They received daily subcutaneous (SC) injections of filgrastim during subdiaphragmatic irradiation. Total white blood cell (WBC) and absolute neutrophil cell (ANC) counts were measured and compared to a historical series of patients, and hematological toxicity was assessed. The endpoints of the study were nadir WBC and ANC counts and time to WBC and ANC recovery.Compared to the historical series, filgrastim significantly increased the WBC and ANC throughout the period of subdiaphragmatic irradiation. Nadir WBC (5.98 +/- 1.24/mm3) and ANC (4.71 +/- 1.07/mm3) in the Filgrastim group were approximately two times those of the historical series (3.32 +/- 1.06/mm3 and 2.39 +/- 0.97/mm3 respectively; p < 0.002). Nadir platelet counts were not affected by filgrastim therapy. Three of seven patients reported mild musculoskeletal pain, but there was no other apparent toxicity.Compared to the historical series, filgrastim therapy significantly increased WBC and ANC during extended field radiation therapy and was well tolerated. It may be clinically useful in other groups of patients who are likely to develop profound neutropenia during large field irradiation.

Abstract

To assess the risk of death from heart disease after Hodgkin's disease therapy.Retrospective study comparing treated patients with a matched general population.Referral center.A total of 2232 consecutive Hodgkin's disease patients treated from 1960 through 1991. Follow-up averaged 9.5 years.Relative risks (RRs), the ratio of the observed to the expected cases with 95% confidence intervals (CIs), chi tests for trends, and Kaplan-Meier actuarial risks.Of the 2232 patients, 88 (3.9%) died of heart disease, 55 from acute myocardial infarction and 33 from other cardiac diseases, including congestive heart failure, radiation pericarditis or pancarditis, cardiomyopathy, or valvular heart disease. The RR for cardiac death was 3.1 (CI, 2.4 to 3.7). Mediastinal radiation of 30 Gy or less (n = 385 patients) did not increase risk; above 30 Gy (n = 1830), RR was 3.5 (CI, 2.7 to 4.3). Blocking to limit cardiac exposure reduced the RR for other cardiac diseases from 5.3 (CI, 3.1 to 7.5) to 1.4 (CI, 0.6 to 2.9), but not acute myocardial infarction (RR, 3.7 vs 3.4). The RRs increased with duration after treatment (trend in acute myocardial infarction, P = .02; in other cardiac diseases, P = .004). The RR for acute myocardial infarction was highest after irradiation before 20 years of age and decreased with increasing age at treatment (P < .0001 for trend).Mediastinal irradiation for Hodgkin's disease increases the risk of subsequent death from heart disease. Risk increased with high mediastinal doses, minimal protective cardiac blocking, young age at irradiation, and increasing duration of follow-up.

Abstract

Cardiac disease is second only to neoplastic disease as a cause of death after treatment for Hodgkin's disease. This study evaluates the risks of cardiac disease following treatment of Hodgkin's disease during childhood and adolescence.We reviewed records of 635 patients treated for Hodgkin's disease before 21 years of age at Stanford University between 1961 and 1991. Mean age was 15.4 years; mean follow-up duration was 10.3 years, representing 6,564 person-years of observation. Relative risks (RRs) of death from cardiac diseases were calculated by comparison with age-, sex-, and race-matched general population rates from United States decennial life-tables.Twelve patients have died of cardiac disease (RR, 29.6; 95% confidence interval [CI], 16.0 to 49.3), including seven deaths from acute myocardial infarction ([AMI] RR, 41.5; 95% CI, 18.1 to 82.1), three from valvular heart disease, and two from radiation pericarditis/pancarditis. Thus far, the risk of AMI death was comparable after radiation alone (RO) or after chemotherapy and radiation (CM) (RO-AMI RR, 52.2; 95% CI, 21.1 to 108.7; CM-AMI RR, 21.1; 95% CI, 0.0 to 104.4; P = .6). The risk for other cardiac death (CD) tended to be higher after combined treatment (RO-non-AMI RR, 7.4; 95% CI, 0.0 to 36.5; CM-non-AMI RR, 45.8; 95% CI, 14.4 to 110.6; P = .1). Deaths occurred 3 to 22 years after patients received 42 to 45 Gy to the mediastinum between 9 and 20 years of age. There have been no deaths among patients treated to lower mediastinal radiation doses or without mediastinal radiation. There are no clear trends in the latency of risk. One hundred six nonfatal abnormalities have also been diagnosed.Mediastinal radiation of 40 to 45 Gy increases the risk of death from coronary artery and other cardiac diseases. The risk increases within 5 years of irradiation. These observations support combined-modality, low-dose irradiation regimens in children and adolescents and suggest the need for careful cardiac screening of treated patients.

Abstract

The purpose of this study was to determine the influence that accurate MR detection of chest wall and pleural disease has on the type and extent of radiation therapy subsequently performed in patients with thoracic lymphoma.MR images and CT scans of the chests of 57 patients who had biopsy-proved lymphoma were retrospectively examined for evidence of involvement of the chest wall and pleura. For patients with thoracic lymphoma, we compared radiation portals and dosage designed by using information from MR images with portals and dosage designed by using information from chest radiographs and CT scans.Chest wall or pleural disease was detected in 22 of the 57 patients examined. Chest wall disease was identified on MR images in 20 patients (29 sites) and pleural disease in 14 patients (16 sites). Chest wall and pleural disease were identified on CT scans in seven and five patients, respectively. Of the 15 patients who received radiation therapy, three (20%) had treatment planning altered, either by increasing the area exposed to radiation or by increasing the radiation dose, because of findings noted only on MR images.Chest wall and pleural sites of disease that may be detected only on MR images can be important in designing appropriate radiation portals and dosage for patients who have chest lymphoma.

Abstract

To assess results, complications, treatment techniques, and patterns of failure in patients with bulky mediastinal Hodgkin's disease treated with combined modality therapy.Between 1980 and 1988, 48 patients with Hodgkin's disease who had large mediastinal masses were treated at Stanford University. All patients were staged with clinical studies which included computed tomographic scans of the chest and bipedal lymphograms. Initially, 10 patients underwent staging laparotomy and splenectomy, subsequently all patients were staged by clinical criteria alone. Mediastinal mass ratios ranged from .35 to .85 (mean .46). The majority of patients had at least one site of extralymphatic extension (E-lesion) within the chest. Combined modality therapy included MOPP (prednisone deleted after mediastinal irradiation) in 15, ABVD in 14, and PAVe in 19 patients. All patients received mantle irradiation (mean dose 44 Gy) but only patients with abdominal disease received subdiaphragmatic irradiation.The actuarial survival and freedom from relapse were 84% and 88% at 9 years. There was an intrathoracic component of failure in all seven patients who either failed to achieve an initial complete response or who experienced a relapse after a complete response. Both patients who experienced a relapse after a complete response achieved durable second responses with subsequent chemotherapy. Two of five patients who failed to achieve an initial complete response were treated successfully with alternative chemotherapy.Routine combined modality therapy is the treatment of choice for patients with Hodgkin's disease who have large mediastinal masses.

Abstract

Most studies of survivors of Hodgkin's disease have shown a low risk for subsequent breast cancer, even though much lower doses of radiation than those used for Hodgkin's disease have been shown to induce breast cancer in other settings.This study quantifies the risk of breast cancer following Hodgkin's disease treatment according to age at treatment and type of treatment.To evaluate the risk of breast cancer from irradiation, we reviewed records of 885 women treated for Hodgkin's disease between 1961 and 1990 (mean follow-up, 10 years). Risks for breast cancer incidence and mortality were calculated by comparison with expected rates for a general female population matched by age and race.Twenty-five patients have developed invasive breast cancer, yielding a relative risk (RR) of 4.1 (95% confidence interval [CI] = 2.5-5.7). An additional patient developed multifocal carcinoma in situ. Age at irradiation strongly influenced risk: RR was 136 for women treated before 15 years of age (95% CI = 34-371). RR declined with age at irradiation (P for trend < .0001), but the elevation remained statistically significant for subjects less than 30 years old at the time of irradiation (for those 15-24, RR = 19 [95% CI = 10.3-32]; for those 24-29, RR = 7 [95% CI = 3.2-14.4]). In women above 30 years of age, the risk was not elevated (RR = 0.7; 95% CI = 0.2-1.8). Risk of breast cancer increased significantly with time since treatment (P for trend < .0001). The RR was 2.0 (95% CI = 1.0-3.5) with follow-up under 15 years and 13.6 (95% CI = 7.9-18.2) with follow-up equal to or exceeding 15 years. The addition of mechlorethamine, vincristine, procarbazine, and prednisone chemotherapy to irradiation increased the risk within the first 15 years. Most breast cancers (22 of 26) arose within or at the margin of the radiation field and were infiltrating ductal carcinomas. Stage distribution and outcome suggest that the increased incidence was not solely attributable to vigilant screening. RR of death from breast cancer was 5.1 (95% CI = 2.2-10.0).Women treated for Hodgkin's disease with radiation before 30 years of age are at markedly increased risk for breast cancer, with risk increasing dramatically more than 15 years after therapy.The high RR for development of breast cancer in women exposed to therapeutic radiation under 30 years of age raises important issues about optimal treatment strategies for patients with Hodgkin's disease, breast cancer, and other cancers.

Abstract

This report describes the efficacy and toxicity of PAVe (procarbazine, Alkeran, vinblastine) and irradiation (RT) in the management of 159 patients with locally extensive or advanced stage Hodgkin's disease (HD) at Stanford University. Patients received six courses of chemotherapy alternating with RT. The extent of RT and the schedule of treatment varied according to the stage of disease. About 2/3 of patients received PAVe/RT in the setting of prospective, randomized clinical trials. The rate of complete response was 93%. With a median follow-up of seven years (range 2-17), the 15 year actuarial freedom from progression (FFP) is 78% and overall survival is 75%. Ten-year FFP by stage is: 80% for locally extensive stage II, 90% for stage IIIA and 70% for stage IIIB. Excellent and equal results were attained with PAVe/RT vs. MOP(P) (mustard, Oncovin, procarbazine with or without prednisone)/RT in the randomized combined modality studies. Progression or recurrence was documented in 30 patients and was more common in irradiated sites. PAVe was well tolerated acutely. There were no treatment related fatalities. Twenty-three (14%) patients were admitted to the hospital for neutropenic fever. Five second malignancies have occurred after PAVe/RT only: one myelodysplastic syndrome, one acute myelogenous leukemia, one non-Hodgkin's lymphoma and two solid tumors including a case of non-small cell lung cancer and an in situ carcinoma of the cervix. Three patients died from myocardial infarction several years after the completion of treatment. These mature data show that PAVe/RT is effective and well-tolerated therapy for locally extensive stage II and IIIA/B HD.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Approximately 20-25% of patients with stage I-II Hodgkin's disease treated initially with irradiation alone will experience a relapse of disease. Restaging at the time of relapse provides a useful prognostic indicator and may help in the selection of salvage therapy. Systemic treatment is indicated in nearly all patients. In the Stanford experience, 109 patients who relapsed were treated with MOPP (or MOPP-like chemotherapy) with or without local irradiation. The actuarial 10-year survival and freedom from second relapse were both 57%. Important prognostic factors included 'relapse stage' (IA vs. II-IIIA vs. I-IIIB or IV) and type of salvage therapy (combined modality vs. chemotherapy alone). Important issues in management of these patients include the selection of chemotherapy agents, whether to incorporate localised irradiation, and the use of even more aggressive salvage treatment programs, such as autologous bone marrow transplantation, in selected patients with a very poor prognosis.

Abstract

The authors report the histories of two patients with undifferentiated carcinoma metastatic to lymph nodes simulating the "syncytial variant" of nodular sclerosing Hodgkin's disease. One of the patients initially was treated for Hodgkin's disease, but the clinical evolution was more typical of carcinoma. Both lesions were characterized histologically by noncohesive aggregates of large neoplastic cells with abundant eosinophilic cytoplasm and conspicuous nucleoli. Although cells compatible with diagnostic Reed-Sternberg cells were identified in an "appropriate" cellular background in both patients, the diagnosis of carcinoma was supported by intense cytokeratin immunoreactivity. Subtle histologic clues that should suggest the possibility of metastatic carcinoma in a patient whose morphologic data suggests the syncytial variant of nodular sclerosing Hodgkin's disease include sinus infiltration, phagocytosis of neutrophils by tumor cells, marked nuclear anaplasia, and the presence of spindle-shaped tumor cells.

Abstract

The ability of postoperative total lymphoid irradiation to reverse otherwise intractable cardiac allograft rejection was examined in a group of 10 patients in whom conventional rejection therapy (including pulsed steroids and monoclonal or polyclonal anti-T-cell antibody therapy) had failed to provide sustained freedom from rejection. Follow-up periods range from 73 to 1119 days since the start of total lymphoid irradiation. No patient died or sustained serious morbidity because of the irradiation. Three patients have had no further rejection (follow-up periods, 105 to 365 days). Two patients died--one in cardiogenic shock during the course of total lymphoid irradiation, the other with recurrent rejection caused by noncompliance with his medical regimen. Total lymphoid irradiation appears to be a safe and a moderately effective immunosuppressive modality for "salvage" therapy of cardiac allograft rejection unresponsive to conventional therapy.

Abstract

Chimeric (murine/human) anti-CD4 monoclonal antibody was infused into seven patients with mycosis fungoides. Successive patients received doses of 10, 20, 40, and 80 mg of antibody twice a week for 3 consecutive weeks. All patients had some clinical improvement, but responses were of relatively short duration. Serum levels of chimeric antibody varied as a function of dose. At the 80-mg dose level, antibody was readily observed in biopsied skin lesions. Although there was coating by antibody of most CD4 positive cells in the blood, there was no significant depletion of CD4 positive cells. Low-level antibody responses against the mouse Ig variable region and human Ig allotypic constant region determinants were observed in several patients, but none were of clinical significance. All but two patients made primary antibody and T-cell proliferative responses to a simultaneously administered foreign protein test antigen. However, there was marked suppression of the mixed lymphocyte reaction. We conclude that at the dose levels studied, a chimeric anti-CD4 monoclonal antibody (1) had some clinical efficacy against mycosis fungoides; (2) was well tolerated; (3) had a low level of immunogenicity; (4) had immediate immunosuppressive effects; and (5) did not induce tolerance to a co-injected antigen.

Abstract

Seventy-seven Hodgkin's disease and non-Hodgkin's lymphoma (NHL) patients received high-dose etoposide in combination with cyclophosphamide and either fractionated total body irradiation (TBI) (n = 28) or carmustine (n = 49) prior to autologous bone marrow transplantation. Marrow from NHL patients was purged in vitro with a panel of monoclonal B- and T-cell antibodies and complement. Six toxic deaths (8%) occurred, all in patients who received carmustine. With a median follow-up of 1 year, 57 patients are alive and free from progressive disease. The 1-year actuarial survival and freedom from progression are 85 and 73% in fractionated TBI/etoposide/cyclophosphamide-treated patients and 79 and 72% in carmustine/etoposide/cyclophosphamide-treated patients. Forty-five of these patients participated in prospective trials for which eligibility criteria were (1) less than 25% curability with conventional therapy; (2) achievement of minimal disease state with conventional therapy; and (3) transplantation early in the course of disease. One-year actuarial survival for 18 patients with relapsed Hodgkin's disease is 80% and for 21 relapsed intermediate and high-grade NHL patients, 70%. One NHL Burkitt's patient was transplanted on a protocol for high-risk intermediate and high-grade NHL in first remission. Five patients with follicular mixed or small cleaved NHL were also transplanted in first remission.

Abstract

Using immunohistochemical methods, the authors studied the expression of pan-T- and majority-T-cell antigens (CD5, CD2, CD3, TCR-beta, CD7) and T-cell subset antigens (CD4, CD8) in cutaneous T cells in mycosis fungoides (MF) (177 biopsies from 124 patients) and a variety of inflammatory lesions (45 biopsies from 45 patients). The authors detected the absence of pan-T- or majority-T-cell antigens, or of both T-cell subset antigens, from T cells in the epidermis but not the dermis in 15 MF biopsies (8%) from 11 MF patients (9%), but in none of the inflammatory skin lesions. The opposite picture, characterized by lack of antigen expression by the dermal T cells only, was not seen in any of the MF or inflammatory lesions. The absence of antigen expression by epidermal but not dermal T cells, which the authors have termed antigen discordance, was most prevalent for CD5, CD7, and TCR-beta, each being discordant in 6% to 7% of MF cases or patients tested. Among the MF biopsies showing antigen discordance, 14 of 15 biospies (93%) from 10 of 11 patients (91%) were discordant for two or more antigens. Antigen discordance was not an artifact of treatment, because none of the patients showing discordance was receiving treatment at the time of their initial discordant biopsy. The discordance was the only immunophenotypic abnormality detected in 8 of 15 (53%) of the discordant MF biopsies. Thus, this antigen discordance was an important diagnostic feature that allowed the immunophenotypic distinction of MF from a variety of inflammatory skin lesions.

Abstract

Mycosis fungoides and the Sézary syndrome are forms of cutaneous T-cell lymphoma. Mycosis fungoides is an uncommon disease: only about 500 new cases are diagnosed in the United States annually. The median age of onset is 55 years and there is a 2:1 male predominance. The etiology of mycosis fungoides is unknown. Although occupational exposures have been implicated, case control studies fail to support this hypothesis. Mycosis fungoides is typified by cutaneous plaques which may evolve into tumors over the course of time. It is often preceded by a lengthy pre-mycotic phase prior to the time of definitive diagnosis. In its earliest diagnostic phase, there may only be slightly scaling patches with a limited distribution. Indurated lesions evolve into plaques, which may become more generalized in their distribution. As the severity of skin involvement increases, there is an increasing likelihood of spread to extracutaneous sites. The pathology of this disease is marked by involvement of the epidermis (Pautrier microabscesses). Immunologic studies characterize these cells as belonging to the helper T-cell subset. Genotypic analysis demonstrates monoclonal rearrangements of the T-cell receptors of the infiltrating cells. The staging system for mycosis fungoides considers the extent of skin involvement, presence of lymph node or visceral disease, and detection of abnormal cells in the peripheral blood. Patients with disease limited to the skin (90% of newly diagnosed cases) are treated best with topical or cutaneous therapies. Common modalities include psoralen photochemotherapy (PUVA), topical chemotherapy (nitrogen mustard) and total skin electron beam therapy. Both topical nitrogen mustard and electron beam therapy have good initial response rates (73% and 100%) and may achieve long-term disease-free survival, especially in patients with initially limited disease. Even if the response is incomplete or relapse occurs, substantial and very important palliation is generally achieved with topical therapy. Recurrent or resistant cutaneous disease will require the use of sequential topical treatment. The median survival time of patients who present with disease limited to the skin is greater than 10 years, and many deaths in this group are from intercurrent causes, especially in patients with limited or generalized plaque disease. If cutaneous tumors are present, the majority of these patients will eventually die from disease-related causes. The prognosis of patients who develop extracutaneous disease is exceedingly poor (median survival time, approximately 1 year).(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract

From July 1981 to July 1985, 20 patients with bulky mediastinal Hodgkin's Disease (maximum mediastinal width divided by the maximum intrathoracic diameter for a mediastinal mass ratio (MMR) greater than 0.33 were treated at Stanford University with definitive radiation therapy alone. The majority of these patients were selected to receive radiation therapy because they had the more favorable characteristics of minimal extralymphatic involvement, mediastinal masses that were superior and central in location, and a MMR less than or equal to 0.50. All 20 patients were laparotomy staged, and 17 received some radiation to the mantle before laparotomy. Seventeen patients had pathologic stage (PS) II disease (13 PS IIA, 4 PS IIB), two had PS IIISA, and one had PS IB. Eleven patients (55%) had extralymphatic involvement. All patients were irradiated to the mantle field using a shrinking field technique (mediastinal dose, 4400 to 5500 cGy, mean 4990 cGy). After completion of the mantle, all patients with good clinical responses received infradiaphragmatic radiation. Treatment complications included two cases of mild radiation pneumonitis, five of hypothyroidism, five of localized Herpes zoster, one of amenorrhea, one of non-Hodgkin's lymphoma, and one of sepsis. Four patients relapsed. All had an intrathoracic component to their failure. All four patients were salvaged with MOP(P) chemotherapy and are currently alive and free of disease. For the entire group, the actuarial freedom from relapse is 80% at 7 years and the survival is 100%. Median follow-up time is 67 months. The authors conclude that radiation therapy alone is effective in the management of selected patients with Hodgkin's disease who have extensive mediastinal involvement, even when the MMR exceeds 1/3.

Abstract

Deficiencies of Leu-8 and CD7 antigens are exhibited by CD3+ T cells in the skin lesions of most patients with mycosis fungoides/Sézary syndrome. To determine whether these antigenic abnormalities are limited to involved skin, we studied Leu-8/CD7 expression in 21 skin lesions of mycosis fungoides/Sézary syndrome obtained from 16 patients and compared them with their peripheral blood leukocytes obtained concurrently. There was no correlation between Leu-8/CD7 values in skin lesions versus blood. Blood values were relatively uniform; most patients had 50% or greater of CD3+, Leu-8+ T cells and CD3+, CD7+ T cells. In contrast, skin values were highly heterogeneous; most patients lacked expression of Leu-8 or CD7 by the majority of lesional CD3+ T cells. Furthermore, Leu-8/CD7 antigen deficiency was present in lesional skin in one patient with mycosis fungoides but not in her concurrently sampled pityriasis lichenoides chronica or blood. These findings suggest that Leu-8/CD7 antigen deficiencies in skin lesions of mycosis fungoides/Sézary syndrome do not represent generalized antigenic abnormalities of CD3+ T cells in other body compartments and that within the skin, these deficiencies are disease specific within individual patients with more than one dermatosis. Comparative peripheral blood immunophenotyping of the patients with mycosis fungoides/Sézary syndrome and of the control subjects indicated that the control ranges of CD3+/Leu-8+ and CD3+/CD7+ T cells (33% or greater) extend lower than reported previously (60% or greater) and suggested that leukemic involvement in patients with mycosis fungoides/Sézary syndrome may correlate with percentages of CD3+, Leu8+ and/or CD3+, CD7+ T cells that fall below the revised control range.

Abstract

Prognostic factors were analyzed retrospectively in 109 patients who relapsed after treatment with radiation only for Hodgkin's disease. Factors analyzed included initial stage, age, time to first relapse, histology, sex, extent of initial irradiation, sites of relapse, relapse stage (RS), average relative dose intensity (ARDI) of chemotherapy, and type of salvage therapy. Ninety-three percent of the patients received either standard or modified mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). With a median follow-up of 8.3 years, the actuarial survival and freedom from second relapse (FF2ndR) was 57% at 10 years. The extent of disease at the time of relapse, or so-called RS was found to be the single most important prognostic factor. Nearly 90% of patients with RS IA or IEA (favorable group) were disease free, and nearly 60% of patients with RS IIA, IIEA, or IIIA (intermediate group) were disease free compared with only 34% of patients with B symptoms or stage IV disease (unfavorable group). In a subset analysis, the use of combined modality therapy (CMT) was associated with an improved FF2ndR and survival in patients from the intermediate and unfavorable relapse groups. Age greater than 50 years was associated with an increased risk of second relapse and a lower survival. The other factors analyzed appeared to be of no independent prognostic value.

Abstract

Allogeneic and autologous BMTs are highly effective and successful treatment modalities for selected patients. Use of BMT earlier in the course of disease yields better results when compared to patients with more advanced disease. Recent advances such as use of cloned growth factors, cytokines, etc..., will continue to contribute to lessen morbidity and mortality. Finally, as investigators understand, prevent, and treat expected side effects from BMTs, the patients' burden in terms of physical, psychological, and financial costs should lessen substantially.

Abstract

Fifteen cases of cutaneous lymphoid hyperplasia were studied immunohistologically with a large panel of monoclonal antibodies to determine their immunoarchitectural composition and to determine whether immunologic criteria recently proposed to identify lymphoma ever occur in benign skin lesions. All lesions were composed of T cells, polytypic B cells, macrophages, and Langerhans cells. Although only six cases containing lymphoid follicles were recognized in routinely stained sections, an additional five were identified in immunoperoxidase-stained sections. These follicles were of both the primary and secondary types and contained dendritic reticulum cell networks. The immunophenotypic features of these follicles were similar to those of reactive follicles in lymphoid organs and contrasted sharply with those reported previously for follicular lymphomas. Helper T cells were predominant in 11 cases. With regard to proposed criteria for T cell lymphoma, we did not detect loss of pan T cell antigens CD2, CD3, CD5, or BF-1, nor did we find populations of T cells with abnormal co-expression or loss of subset antigens such as CD4-8- or CD4+8+. Two cases in which relatively sparse infiltrates were present, however, were moderately CD7-deficient. This finding suggests that the CD7 criterion for cutaneous T cell neoplasia be modified in this situation. As observed previously, Leu-8 antigen deficiency was a common, nonspecific finding. With regard to proposed criteria for B cell lymphoma, we did not detect populations of B cells that were immunoglobulin-negative, nor did we observe preferential loss of one or more B-lineage antigens, histocompatibility complex-associated antigens, or lymphocyte function-associated antigens. We also did not identify any CD5+ B cells. On the basis of a comparison of our current data with prior studies of cutaneous lymphomas, we conclude that the immunologic findings recently proposed as general criteria for the differentiation of lymphoma from lymphoid hyperplasia are, in fact, applicable to cutaneous lymphoid lesions.

Abstract

Treatment with total lymphoid irradiation (TLI) and corticosteroids markedly reduced activity of systemic lupus erythematosis in 10 patients with diffuse proliferative lupus nephritis (DPLN) complicated by a nephrotic syndrome. Physiologic and morphometric techniques were used serially before, and 12 and 36 mo post-TLI to characterize the course of glomerular injury. Judged by a progressive reduction in the density of glomerular cells and immune deposits, glomerular inflammation subsided. A sustained reduction in the fractional clearance of albumin, IgG and uncharged dextrans of radius greater than 50 A, pointed to a parallel improvement in glomerular barrier size-selectivity. Corresponding changes in GFR were modest, however. A trend towards higher GFR at 12 mo was associated with a marked increase in the fraction of glomerular tuft area occupied by patent capillary loops as inflammatory changes receded. A late trend toward declining GFR beyond 12 mo was associated with progressive glomerulosclerosis, which affected 57% of all glomeruli globally by 36 mo post-TLI. Judged by a parallel increase in volume by 59%, remaining, patent glomeruli had undergone a process of adaptive enlargement. We propose that an increasing fraction of glomeruli continues to undergo progressive sclerosis after DPLN has become quiescent, and that the prevailing GFR depends on the extent to which hypertrophied remnant glomeruli can compensate for the ensuing loss of filtration surface area.

Abstract

Using immunohistologic methods, we studied the expression of the T-cell receptor (TCR)-associated antigens CD3, TCR-beta, and TCR-delta by cutaneous T cells in mycosis fungoides (MF) (36 patients) and a variety of inflammatory diseases (16 patients). Most T cells in the inflammatory diseases and patch/plaque mycosis fungoides expressed the immunophenotype characteristic of the vast majority of mature peripheral T cells: CD3+ TCR-beta+ TCR-delta-. In contrast, abnormal CD3/TCR-beta antigen expression was seen in 3 of 6 cases (50%) of tumor stage mycosis fungoides. Furthermore, we were able to document its evolution from the normal pattern present in earlier patch/plaque lesions of the two cases in which serial biopsies were available for study. Divergence of epidermal versus dermal CD3/TCR-beta antigen expression was seen in 2 of 34 (6%) of biopsies of patch/plaque mycosis fungoides but not in inflammatory controls. The TCR-delta+ cells were generally rare regardless of diagnosis. We conclude that inflammatory skin diseases and most patch/plaque mycosis fungoides are typically composed of T lymphocytes that resemble mature peripheral T cells in regard to their expression of TCR-associated antigens. In contrast, aberrant patterns of TCR-associated antigen expression can be seen in tumor stage MF, and, more rarely in patch/plaque MF.

Abstract

Cutaneous lymphoid hyperplasia (CLH) is a disorder characterized by the development of one or more skin lesions containing dense lymphoid infiltrates that exhibit the histopathologic features of a benign, reactive process. Nevertheless, some cases have been associated with the subsequent development of clinically overt lymphomas. This suggests that monoclonal populations may exist in some cases of CLH and that these cases may represent a subset more likely to evolve into lymphoma. To determine if such a subset of CLH can be distinguished, Southern blot analysis of DNA was used to study the immunogenotypic features of lesions from 14 patients with clinical, histopathologic, and immunopathologic findings characteristic of CLH. Five cases exhibited detectable clonal rearrangements of immunoglobulin genes. Furthermore, one of these five cases evolved into overt diffuse large cell lymphoma of B cell lineage during a 2-year follow-up of recurrent disease at the original cutaneous site. The immunoglobulin gene rearrangements of this lymphoma were identical to those of the prior CLH lesion. There was no evidence of detectable t(14;18) chromosomal translocations or clonal rearrangements of the beta gene of the T cell receptor in any case. It was concluded that CLH can be divided into two subsets based on the presence or absence of a clonal B cell population, and that overt lymphoma can arise from the former subset and contain the same B cell clone identified in the pre-existent CLH lesion.

Abstract

Patients with Hodgkin's disease who have a large mediastinal mass present a challenge to the oncologist. Individualized therapy is often a key consideration for the management of these patients. Careful clinical staging is essential to develop the most effective treatment plan. The majority of these patients may be treated most effectively with combined modality therapy; however, a carefully selected group may be treated successfully with irradiation alone. Close follow-up is helpful to detect early relapse or manage complications of therapy.

Abstract

A preliminary study was performed to evaluate the effectiveness of narrow-band filtration of backscattered ultrasound for the detection of splenic involvement in patients with Hodgkin disease. Regions of interest were identified in the spleens of 14 normal volunteers and eight Hodgkin disease patients before staging laparotomy. An analysis of the narrow-band-filtered waveforms showed that the mean amplitudes of the filtered ultrasonic signals received correlated with the presence of extensive splenic involvement with Hodgkin disease (defined as more than four grossly visible nodules on cut section) (p = .0004). Conversely, mean amplitudes of unfiltered ultrasonic backscatter, employed in conventional sonographic imaging, did not correlate with splenic involvement (p = .5). Phantom studies were performed to develop a tissue model for the observed phenomena; images of the phantoms and of the involved and uninvolved spleens were made by using techniques involving narrow-band filtration of backscattered ultrasound. Our results indicate that narrow-band-filtered sonography holds promise for detecting lymphomatous involvement of the spleen, although larger studies, with equipment allowing real-time implementation of narrow-band filtering, are needed.

Abstract

The clinical course of 54 patients with small lymphocytic lymphoma (SL) was reviewed. The majority of patients had disseminated lymphoma at the time of diagnosis; 14 patients (26%) presented with Ann Arbor stage I and II disease. Five- and 10-year survival for all patients was 76% and 49%. The only clinicopathologic features identified that predicted a shortened survival were the presence or absence of systemic (B) symptoms (15% v 63% at 10 years, P = .01) and a diffuse rather than pseudofollicular nodal architecture (47% v 87% at 10 years, P = .04). Initial bone marrow involvement was not an adverse prognostic factor for patients who presented with stage III and IV disease. Ten patients developed a marked lymphocytosis consistent with progression to a leukemic phase (chronic lymphocytic leukemia [CLL]). These ten patients had a median initial lymphocyte count of 2,790, compared with 1,580 for those patients who did not progress to CLL (P = .0001). Developing CLL did not adversely affect survival (P = .48). Thirty-seven patients were treated with various combinations of radiation and chemotherapy; 17 patients received no initial therapy. Ten-year freedom from relapse (FFR) for stage I and II patients treated with irradiation was 80% and 62%; FFR for stage III and IV treated patients was 11%. Despite the marked differences in FFR, no statistically significant difference in survival could be demonstrated between the various stages. Selected patients with advanced SL received no initial therapy; these patients had a 10-year survival that was not statistically different from the immediately treated stage III and IV patients. Patients with stage I and II SL should be treated with irradiation; prolonged FFR and possibly cure of the disease can be achieved in these patients.

Abstract

Involvement of the peripheral blood in mycosis fungoides/Sezary syndrome (MF/SS) has a significant impact upon prognosis, but it is often difficult to distinguish circulating cells of MF/SS from atypical reactive lymphocytes. We compared the standard morphologic method of identifying leukemic cells, the Sezary preparation, to a genotypic method using Southern blot analysis of T-cell receptor gene rearrangements in concurrent blood samples. We studied 26 MF/SS patients, five of them in remission, together with five controls from cases of various non-MF/SS skin diseases. Six of 26 MF/SS patients had morphologically atypical circulating leukocytes (3%, 4%, 5%, 14%, 16%, 19%). Seven of 26 MF/SS patients had clonal T-cell receptor gene rearrangements, including the four patients with the greatest percentages of atypical cells and three patients lacking atypical cells. Six of seven patients had skin disease at the time of sampling, including three with erythroderma, two with generalized thick plaques, and one with generalized patches, while one patient was in clinical remission. All five controls lacked morphologic and genotypic evidence of atypical or clonal T-cells. Relative to genotyping, in our series the Sezary preparation was less sensitive and less specific. There were three apparent false negative results in the Sezary preparations, and two potential false positive (patients with 3% and 4% atypical leukocytes); however, there was agreement between the two techniques in most cases. We conclude that gene rearrangement studies may provide an effective test with which to assess the peripheral blood of MF/SS patients.

Abstract

This prospective study assesses the contribution of lymphography (LAG), abdominal-pelvic computed tomography (CT), and bone marrow biopsy to the staging and management of 168 consecutive cases of newly diagnosed non-Hodgkin lymphoma (NHL). LAG and/or CT influenced Ann Arbor clinical stage (CS) in 39 patients (23%) and Ann Arbor pathologic stage (PS) in 23 patients (14%) by detection of clinically inapparent retroperitoneal adenopathy and/or extranodal disease. LAG findings raised the CS in eight patients and the PS in six of the eight by showing adenopathy when the CT results were negative. By depicting extranodal disease, CT resulted in the CS being raised in an additional ten patients and the PS in six of the ten. Of the diagnostic tests assessed, bone marrow biopsy and/or cytology had the greatest influence on staging. Clinical staging that included LAG/CT resulted in the identification of only 30 patients with CS IV disease, whereas an additional 53 CS I through CS III patients had their disease stage raised to PS IV due to positive bone marrow biopsy/cytology results. However, 42 of the 53 patients already had advanced (CS III) disease. Initial case management was influenced by LAG, CT, or bone marrow biopsy/cytology results in 27 of 168 patients. LAG/CT results influenced management in 20 of 27 cases, while bone marrow biopsy/cytology results caused initial management changes in only seven of the 27 cases.

Abstract

Between July 1968 and July 1986, 915 patients with clinical stage (CS) I and II Hodgkin's disease limited to sites above the diaphragm underwent laparotomy and splenectomy at Stanford University. Fifteen percent were CS I, of whom 76% had cervical/supraclavicular disease, 13% axillary disease, and 9% mediastinal presentations. CS I patients were more likely to be male, were significantly older, and were significantly less likely to have nodular sclerosis (NS) histology than CS II patients. Twenty percent of CS I patients and 30% of CS II patients were pathologically upstaged. No CS I patients were upstaged to pathological stage (PS) IV. Univariate and multivariate analyses of presenting clinical characteristics were performed to predict staging laparotomy findings. CS I women, CS I patients with mediastinal-only disease, and CS I men with either lymphocyte predominance or interfollicular histologies were at low risk for having disease below the diaphragm (5%) or requiring chemotherapy (0%). CS II women who were less than 27 years old and had only two or three sites of disease were also at low risk for upstaging (9%) or requiring chemotherapy (2%). Mixed cellularity histology and male gender were associated with increased risk for subdiaphragmatic disease and require laparotomy; the presence of systemic symptoms was not correlated with laparotomy findings. These results confirm the importance of performing staging laparotomy for the majority of patients who present with supradiaphragmatic Hodgkin's disease if treatment programs are based on the presence and extent of subdiaphragmatic disease. Selected subgroups are at low risk for subdiaphragmatic disease and might be spared laparotomy if they are treated with mantle, paraaortic, and splenic irradiation.

Abstract

Sixty-seven patients with favorable pathologic stage (PS) I and IIA or B or IIIA Hodgkin's disease were randomized to receive subtotal or total lymphoid irradiation (STLI/TLI) alone or involved field irradiation (IF) plus six cycles of a novel adjuvant chemotherapy containing vinblastine, bleomycin, and methotrexate (VBM). With a follow-up from 6 to 72 months (median, 37 months), the actuarial freedom-from-progressive disease (FFP) at 5 years is 70% after STLI/TLI and 95% after IF plus VBM. One death has occurred in the irradiation-only treatment group. The data for IF plus VBM are significantly superior to previous actuarial results at 5 years using IF alone (FFP = 35%, P less than .00001) and compare favorably with prior results with IF plus nitrogen mustard, vincristine, procarbazine, +/- prednisone (MOP[P]) chemotherapy (FFP = 80% at 5 years, P = .10). VBM is well tolerated with greater than 90% of calculated doses delivered. As anticipated, VBM has had relatively little adverse effect on male or female fertility. Selected pulmonary functions are reduced early after IF plus VBM to a greater degree than with irradiation of the mediastinum alone, but the differences are modest. Based upon our current numbers and follow-up, we can be 90% confident that VBM as an adjuvant to irradiation in favorable Hodgkin's disease is as effective, or even superior, to MOP(P) chemotherapy. Because of its lesser toxicity, adjuvant VBM may have a broader role in the management of Hodgkin's disease.

Abstract

In order to determine if immunohistologic features are useful in distinguishing benign from malignant types of erythroderma, we studied the immunophenotype of lesional T cells in 20 patients (8 mycosis fungoides/Sézary syndrome, 12 benign) and found them to be generally similar. In all cases, the majority of T cells were Leu-1+, Leu-4+, and Leu-5+, as is typical of mature T cells. Although in most cases a majority of Leu-3+ (helper/phenotype) T cells were present, in 2 there was a majority of the Leu-2+ (cytotoxic/suppressor) subset and in 12 others, a significant minority (20%-40%) of these cells. Low percentages of Leu-2+ cells (less than or equal to 10%), resulting in high Leu-3+/Leu-2+ ratios, did not distinguish benign from malignant erythroderma. Leu-8 antigen deficiency was common in both mycosis fungoides/Sézary syndrome and benign cases (62% vs 75%, respectively). In contrast, Leu-9 antigen deficiency was present in only one patient in each group. The lack of combined Leu-8/9 antigen deficiency in our patients may be due to a heavy inflammatory T cell component, obscuring the antigen deficiencies seen in most nonerythrodermic mycosis fungoides cases. We conclude that immunophenotypic studies with the use of the current antibody panel show many similarities between benign and malignant forms of erythroderma, as well as some minor differences that may prove diagnostically useful if corroborated by future studies.

Abstract

Between January 1978 and December 1986, 94 patients with Stage I-II large cell lymphoma were evaluated at Stanford University Medical Center and treated with a combination of chemotherapy (CTX) and irradiation (XRT). The predominant histology was diffuse large cell (78), followed by immunoblastic (7), follicular large cell (6), and diffuse mixed small and large cell lymphoma (3). Twenty-three patients had Stage I and 71 had Stage II disease. Fifty-one had extranodal involvement (13 IE, 38 IIE), and 11 had B symptoms (2 IB, 9 IIB). Lymphoma was supradiaphragmatic in 58 patients, infradiaphragmatic in 21, and only in extranodal sites in 15. Patients received either involved (81) or extended (13) field XRT with a median dose of 40 Gy and combination CTX with 2 to 9 cycles (median 6) of either CHOP (68), M-BACOD (8), C-MOPP (8), MACOP-B (4), or other (6). Seventy-two patients remain with no evidence of disease, 21 are dead with disease, and one suffered an intercurrent death. Among the 19 patients who relapsed, there were six failures within the XRT field only, two within and outside the XRT field, and 11 outside of the XRT fields only. Actuarial survival and freedom from relapse (FFR) for the entire population were 74% and 72% at 5-years, respectively (33 month median follow-up). Stage I patients achieved 81% survival and 78% FFR, and Stage II patients had 72% survival and 70% FFR. In univariate and multivariate analyses, a favorable outcome was associated with the CTX-XRT-CTX sequence of therapy (p = 0.001), low LDH (p = 0.01), and small tumor bulk (p = 0.04). There were no relapses or deaths among the 21 patients receiving the "sandwich" sequence (CTX-XRT-CTX) of therapy. This series may serve as a comparison with single modality treatment programs for localized large cell lymphoma using either XRT or CTX alone.

Abstract

To assess long-term differences in mortality associated with initial Hodgkin disease therapy.Retrospective review of patients treated in prospectively randomized clinical trials.Three hundred twenty-six patients with pathologic stage I, II, or III, A or B Hodgkin disease treated between 1967 and 1980 with median follow-up exceeding 14 years.Patients at the same stage of disease were randomized to receive radiation alone (167 patients) or radiation followed by 6 cycles of mechlorethamine hydrochloride, vincristine, procarbazine, and prednisone (MOPP) chemotherapy (159 patients) with additional therapy for progression or recurrence.No significant differences between treatment regimens for actuarial survival, intercurrent disease, or Hodgkin disease mortality were seen. Thirty-three patients who received radiation alone and 30 patients who received adjuvant chemotherapy died without evident Hodgkin disease. Death was caused by second neoplasms in 28 patients (relative risk, 2.35; 95% CI, 1.46 to 3.24). Six patients developed acute myelogenous leukemia or a myeloproliferative disorder after treatment including MOPP. Chemotherapy exposure varied among the 8 patients with lung cancers, 6 with gastrointestinal and 3 with other adenocarcinomas, 3 with sarcomas, 1 with diffuse large cell lymphoma, and 1 with melanoma. Acute myocardial infarction caused 9 of 17 cardiovascular disease deaths with 5 occurring in patients between the ages of 33 and 43. Nonetheless, the risk for acute myocardial infarction was not clearly increased (relative risk, 0.86; 95% CI, 0.42 to 1.57). Fifteen patients died from infection: 5, opportunistic; 5, asplenic sepsis; and 5, other pneumonias. Two patients died in accidents, and 1 died from radiation pneumonitis.Adjuvant MOPP chemotherapy improved freedom from relapse without significant survival benefit or impairment. Leukemogenesis was the only lethal complication associated with MOPP. Survivors of Hodgkin disease had an increased risk for death from a second neoplasm, but no apparent increased risk for death from acute myocardial infarction.

Abstract

Seventeen patients with intractable lupus nephritis and nephrotic syndrome were treated with total lymphoid irradiation. Statistically significant improvement in mean renal disease and serologic activity parameters occurred within 3 months and persisted for at least 3 years. Although there was a marked reduction of T helper cell numbers and function after total lymphoid irradiation, recovery of these parameters was not associated with a return of disease activity. Risks of sterility, severe infections, and hematologic malignancy appeared to be lower than with alkylating agents.

Abstract

Twenty-five recipients of cadaveric renal transplants were given total lymphoid irradiation (TLI), perioperative antithymocyte globulin, and low-dose prednisone as the sole maintenance immunosuppressive drug. Nine patients were diabetic, and follow-up was between 19 and 37 months. One-year graft and patient survival was 76% and 87%, respectively, Serious complications included four deaths from cardiovascular disorders, and two deaths from viral infections. Studies of peripheral blood T cell subsets showed a prolonged reduction in the absolute number of helper (Leu-3+) cells, and a rapid recovery of cytotoxic/suppressor (Leu-2+) cells. Analysis of the latter subset, using the monoclonal antibody 9.3, showed that the ratio of suppressor/cytotoxic cells was approximately 10:1. The normal ratio is 1:1. The mean mixed leukocyte reaction remained below 30% of the pre-TLI value for 6 months, and approached 80% at two years. Similar kinetics were observed in the proliferative response to mitogens. The results show that maintenance immunosuppressive drug therapy can be reduced after TLI as compared with conventional drug regimens that use prednisone in combination with cyclosporine and/or azathioprine.

Abstract

We studied the immunohistologic findings of skin biopsy specimens from 21 patients with poikiloderma (14 with mycosis fungoides [MF] and seven with atrophic large-plaque parapsoriasis [ALPP]). Both types of poikiloderma were similar with regard to T-cell antigen expression. In each case, most T cells expressed the CD4+ (helper/inducer) phenotype and lacked Leu-8 antigen. T cells were also deficient in Leu-9 antigen in most cases (MF, 11/14 [79%]; ALPP, 4/7 [57%]). These T-cell antigen deficiencies are similar to those described previously in various types of MF and indicate that such deficiencies are common in minimally infiltrated, patch-stage MF lesions. Because combined Leu-8/Leu-9 antigen deficiencies are uncommon in inflammatory skin diseases, our findings are consistent with the view that ALPP is an early form of MF, as had been suggested previously by results of clinicopathologic studies.

Abstract

The nodular form of lymphocyte predominance Hodgkin's disease has been shown to be immunophenotypically distinct from the histologically diffuse form and from other types of Hodgkin's disease. We undertook a clinicopathological study of 73 cases to determine whether any clinical differences between the nodular and diffuse subtypes could be discerned. Patients with the diffuse form (n = 41) tended to have a course similar to that of other types of Hodgkin's disease; there were few relapses and only two deaths due to Hodgkin's disease. In contrast, patients with the nodular form (n = 32) had significantly more relapses, which were independent of stage or treatment and equally distributed up to 10 years after initial therapy. Despite the frequent relapses, patients with the nodular form had an indolent course, and there was only one death due to Hodgkin's disease. There were seven fatal second cancers and two non-neoplastic treatment-related deaths, equally distributed between the nodular and diffuse groups. We conclude that nodular lymphocyte predominance Hodgkin's disease may have important clinical as well as immunophenotypic differences from other forms of Hodgkin's disease, and that patients with this condition should be followed carefully because of the possibility of late relapse.

Abstract

Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation. After radiotherapy, there was a marked decrease in the number and function of peripheral blood helper/inducer (Leu-3+) T lymphocytes, in the spontaneous secretion of interleukin-1 by synovial biopsy specimens, and in the activity of the joint disease. In contrast, levels of IgM, IgA, and IgG rheumatoid factors and C3 concentrations in blood and synovial fluid samples did not change significantly after therapy with total lymphoid irradiation.

Abstract

The non-Hodgkin's lymphomas include a broad range of neoplasms derived from the T cells and B cells and their precursors in the lymphoid system. Although they are not among the most common cancers, the lymphomas have engendered a great deal of interest among researchers because of their interesting biology and responsiveness to therapy. The non-Hodgkin's lymphomas include at least ten major subtypes of diseases with different morphologic characteristics and clinical behavior. Based upon survival characteristics, it is convenient to divide the lymphomas into three broad categories, low grade, intermediate grade, and high grade. The low grade lymphomas usually arise in middle age or older individuals (median age, 55 years). They are derived from B cells and often have a follicular architectural pattern. They usually present with advanced stages of disease, often by virtue of bone marrow involvement. Nevertheless, patients are usually asymptomatic and may even have spontaneous regressions of disease. These lymphomas are responsive to a broad range of therapies including irradiation, single agent or multi-agent chemotherapy, or combined modality therapy. They are also affected by treatment with biologicals such as alpha interferon and monoclonal antibodies. Unfortunately, response to any of these therapies is often transient and relapse is common. The intermediate grade lymphomas include the common large cell lymphomas (follicular or diffuse) and diffuse mixed cell lymphoma. The lymphomas, together with the high grade immunoblastic lymphoma, are often grouped together for the development of management strategies. These lymphomas may be derived from B cells or T cells. They occur over a broader age range than the low grade lymphomas and they are much more aggressive in their natural behavior. Effective treatment programs have been developed for both limited and advanced clinical stages of disease. In limited disease, moderately intensive chemotherapy is often combined with involved field irradiation. In advanced stage disease, more aggressive combination chemotherapy programs are usually employed. From 40% to 80% of patients may be cured with these approaches, depending upon the initial extent of disease. Two types of high grade lymphoma-lymphoblastic and small noncleaved cell are particularly aggressive in their behavior. Lymphoblastic lymphoma is a T cell lymphoma that often arises in adolescent males and presents with a large mediastinal mass, marrow, and CNS involvement. It closely resembles acute lymphoblastic leukemia (ALL) and similarly intensive chemotherapy programs as are utilized in ALL may be successful in its management.(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract

Twenty patients with solitary plasmacytoma of bone were treated by radiation therapy. Local control was achieved in 19 and most patients developed systemic myeloma. To evaluate disease progression, 65 patients, including 45 from published series, were analyzed. Younger patients seemed less likely to progress (P = .06), but other clinical characteristics including site of involvement and paraprotein status did not influence progression. After dissemination, patients had a clinical course similar to patients with stage I myeloma, with a median survival of 47 months. Overall, patients with solitary plasmacytoma of bone had an indolent course of disease, with a median survival of 10.7 years and a 5-, 10-, and 20-year survival of 75%, 52%, and 37%, respectively.

Abstract

The technique of treatment, response rate, freedom from relapse, survival, and complications of therapy in 123 patients treated with topical nitrogen mustard (HN2) for cutaneous mycosis fungoides (MF) at Stanford University Medical Center are reviewed. Patients were treated with HN2 in an aqueous or ointment base with equal efficacy. Response rates depended on the extent of skin involvement. In limited plaque (T1) disease, complete and overall response rates were 51% and 88%, respectively, while in generalized plaque (T2) disease they were 26% and 69%. No patients with tumorous involvement (T3) achieved complete skin clearance and all 13 of these patients developed progression of disease. Only two of nine patients with erythrodema (T4) achieved a complete response (CR), and both later relapsed. After achieving a CR, 40% of patients with T1 disease and 60% with T2 disease later relapsed; however, subsequent therapies, including repeat courses of topical HN2, often were successful in achieving later skin clearance. Overall, 42% of T1 patients and 31% of T2 patients were without evidence of MF at last follow-up. When death occurred, it was usually unrelated to MF in the T1 group. However, half of the deaths of patients with T2 disease were attributable to MF. Among the 22 patients with T3 or T4 disease, 80% of deaths were attributable to MF. The most common complication observed was a cutaneous hypersensitivity reaction, which occurred much more commonly with the aqueous than the ointment preparation. Fourteen patients (11%) developed subsequent cutaneous malignancies.